2-azabicyclo [3.2.2] ron-6-ene-8, 9-dicarboximides



United States Patent "ice 3,268,553 2-AZABICYCLO[3.2.2]RON-6-ENE-8,9-DICARBOXIMIDES Leo A. Paquette, Portage Township, Kalamazoo County,

Mich, assignor to The Upjohn Company, Kalamazoo, Mich., a corporation ofDelaware No Drawing. Filed July 24, 1963, Ser. No. 297,217 5 Claims.(Cl. 260-326) This invention relates to novel compositions of matter andto methods for producing them. In particular, this invention relates tonovel 2 azabicyclo[3.2.2]non 6 ene 8,9 dicarboximides of the formulas:

wherein R and R are alkyl of l to 4 carbon atoms, inclusive, wherein Rand R are selected from the group consisting of hydrogen and alkyl of 1to 4 carbon atoms, inclusive, wherein R is selected from the groupconsisting of hydrogen, lower alkyl, alkenyl of 3 to 6 carbon atoms,inclusive, alkynyl of 3 to 6 carbon atoms, inclusive, cycloalkyl of 5 to10 carbon atoms, inclusive, and aralkyl of 7 to 11 carbon atoms,inclusive, wherein R is selected from the group consisting of loweralkyl, phenyl, lower alkylphenyl, and di lower alkylphenyl, wherein R isselected from the group consisting of dilower alkylamino and theheterocyclic moieties, aziridinyl, azetidinyl, pyrrolidinyl, piperidino,hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino,and thiomorpholino, each of said heterocyclic moieties having attachedas substituents on carbon atoms thereof zero to 3 lower alkyls,inclusive, wherein n is 2 to 6, inclusive, wherein N and R are separatedby a chain of at least 2 carbon atoms, and wherein the nitrogen atom ofR is attached to a carbon atom of C H The several alkyl groups which areor can be associated with a compound of Formula I, Formula II, orFormula III Patented August 23, 1966 allyl, 2-methyl-2-butenyl,l-methylallyl, 3-methyl-2-butenyl, 2-methylallyl (methallyl) 3-pentenyl,

Z-butenyl (crotyl), 3-butenyl, 1,2-dimethylallyl,

2,3 -dimethyl-2-butenyl, 1,3 -dimethyl-2-butenyl, l-ethyl-2-butenyl,Z-ethylallyl, 4-methyl-2-pentenyl, 1-methyl-2-butenyl, S-hexenyl,

and the like. Examples of alkynyl of 3 to 6 carbon atoms, inclusive,are:

-p py y (p p y 1-methyl-2-propynyl,

S-pentynyl, 1,2-dimethyl-3 -butynyl,

Z-butynyl, 4-pentynyl, B-butynyl, 2-methyl-3 -pentynyl,l-methyl-Z-butynyl, S-hexynyl,

1-methy1-3-butynyl,

and the like. Examples of cycloalkyl of 5'to 10 carbon atoms, inclusive,are:

cyclopentyl, 4-propylcyclohexyl, cyclohexyl, 2,3-dimethylcyclohexyl,2-methylcyclopentyl, 2-methyl-4-ethylcyclohexyl, Z-methylcyclohexyl,cycloheptyl, 3-methylcyclohexyl, 3-ethylcycloheptyl, 4-methylcyclohexyl,cyclooctyl,

2-ethylcyclopentyl, 3-ethylcyclopentyl,

4-tert-butylcyclohexyl, 2,3-dimethylcyclooctyl,

' 3-ethylcyclohexyl, cyclononyl, 2-propylcyclopentyl, cyclodecyl,3-isopropylcyclopentyl,

and the like. Examples of aralkyl of 7 to 11 carbon atoms, inclusive,are:

benzyl, 4-phenylbutyl, phenethyl, l-naphthylmethyl, Z-phenylpropyl,2-naphthylmethyl,

3-phenylpropyl,

and the like. Examples of lower-alkylphenyl are the isomeric forms of:

tolyl, butylphenyl, ethylphenyl, pentylphenyl, propylphenyl,hexylphenyl,

and the like. Examples of di-lower-alkylphenyl are the isomeric formsof:

and the like. Examples of heterocyclic moieties within the scope of R inaddition to those already mentioned above, are:

Z-methylaziridinyl, 2-ethylaziridinyl, 2-butylaziridinyl,2,3-dimethylaziri'dinyl, 2,2-dimethy1aziridinyl,

B-butylpyrrolidinyl, 2-isohexylpyrrolidinyl, 2,S-dimethylpyrrolidinyl,2,2-dimethylpyrrolidinyl, 2,5 -diethylpyrrolidinyl,

3 -tert-butylpyrrolidinyl,

2,3 ,5 -trimethylpyrrolidinyl, 3 ,4-dioctylpyrrolidinyl,Z-methylpipcridino, 3-methylpiperidino, 4-methylpiperidino,

3 -isopropylpiperidino, 4-tert-butylpiperidino,

Z-methylazetidinyl,

3 -methylazetidinyl, 2-octylazetidinyl, 2,2-dirnethylazetidinyl,

3 ,3 -diethylazetidinyl, 2,4,4-trimethylazetidinyl, 2,3,4-trimethylazetidinyl, 2-methylpyrrolidinyl,2-methyl-S-ethylpiperidino, 3 ,5 -dipentylpiperidino,2,4,6-trimethylpiperidino, 2,6-dimethyl-4-octylpiperidino, 2,3 ,5-triethylpiperidino, 2-ethylhexahydroazepinyl,4-tert-butylhexahydroazepinyl, 3-heptylhexahydroazepinyl,2,4-dimethylhexahydroazepinyl, 3,3 -dimethylhexahydro azepinyl,2,4,6-tripropylhexahydroazepinyl, 2-methylheptamethylenimino,S-butylheptamethylenimino, 2,4-diisopropylheptamethylenimino, 3,3-diethylheptamethylenimino, 2,5,8-trirnethylheptamethylenimino,3-methyloctamethylenimino, 2,9-diethyloctamethylenimino,4-isooctyloctamethylenimino, 2-ethylmorpholino,2-methyl-5-ethylmorpholino, 3,3-dimethylmorpholino,2,6-di-tert-butylmorpholino, 3-methylthiomorpholino,2,Z-diethylthiomorpholino, 2,6-dihexylthiomorpholino,

and the like. In each of the above examples of heterocyclic moieties,the free valence, and hence the point of attachment to a carbon atom ofC H in Formula II is on the heterocyclic nitrogen atom. Examples ofsuitable C H bridges are:

and the like. The point of attachment of the nitrogen atom of the2-azabicyclo[3.2.2]non-6-ene-8,9-dicarhoximide moiety in compounds ofFormula II can be at either end of the above examples of C,,H

The novel 2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximides of Formulas Iand II are amines and exist either in the nonprotonated (free base) formor the protonated (acid addition salt) form depending on the pH of theenvironment. They form stable protonates, i.e., acid addition salts, onneutralization with suitable acids, for example, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, acetic, benzoic, salicylic,glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic,methanesulfonic,

cyclohexanesulfamic, picric, and lactic acids, and the like. The FormulaII compounds form both monoand diacid addition salts. The acid additionsalts are useful for upgrading the free bases. The free bases are usefulas acid acceptors in neutralizing undesirable acidity or in absorbing anacid as it is formed in a chemical reaction, for example, adehydrohalogenation reaction in which hydrogen and chlorine, bromine, oriodine are removed from vicinal carbon atoms.

The novel free bases of Formulas I and II form salts with fluosilicicacid which are useful as mothproofing agents according to US. Patents1,915,334 and 2,075,359. They also form salts with thiocyanic acid whichcondense with formaldehyde to form resinous materials useful as picklinginhibitors according to US. Patents 2,425,320 and 2,606,155.

The Formula I and Formula II compounds of this invention also form saltswith penicillins. These salts have solubility characteristics whichcause them to be useful in the isolation and purification ofpenicillins, particularly benzyl penicillin. Said salts can be formedeither by neutralization of the free base form of a compound of FormulaI or Formula II with the free acid form of a penicillin, or by ametathetical exchange of the anion of an acid addition salt of acompound of Formula I or Formula II, for example, the chloride ion of ahydrochloride, with the anionic form of a penicillin.

The novel free bases of Formulas I and II are useful as catalysts forreactions between isocyanates and active hydrogen compounds, e.g.,alcohols and amines, and are especially useful as catalysts for theformation of polyurethanes, e.g., polyurethane foams, by interaction ofpolyisocyanates and polyhydroxy compounds.

The novel compounds of Formulas I and II also form useful quaternaryammonium salts. For example, they form alkyl quaternary ammonium saltsby reaction with an alkyl halide, for example, an alkyl chloride,bromide, or iodide, or by reaction with an alkyl nitrate, an alkalimetal alkyl sulfate, a dialkyl sulfate, an alkyl arylsulfonate, and thelike. The anion of the quaternary ammonium salt can be inorganic, forexample, chloride, bromide, iodide, nitrate, sulfate, phosphate, and thelike, or it can be organic, for example, methosulfate,p-toluene-sulfonate, l-naphthalenesulfonate, acetate, benzoate,salicylate, hydrocinnamate, succinate, lactate, and the like.

The higher alkyl quaternary ammonium salts of the novel Formula I andFormula II 2-'azabicyclo[3.2.2] non- 6-ene-8,9-dicarboximides, forexample, wherein the alkyl group is of 9 to 20 carbon atoms, inclusive,exhibit valuable surface-active and cation-active wetting andemulsifying properties, and also exhibit valuable 'bacteriostatic andbactericidal activity. These higher alkyl quaternary ammonium salts areuseful as detergent-sanitizers and can be employed to sanitize equipmentused in the processing and preparation of foods, for example, fruit,meat, milk, and the like.

The free base form and the acid addition salt form of compounds ofFormula I and Formula II are useful as intermediates in the preparationof said alkyl quaternary ammonium salts.

The novel 2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximides of Formulas I,II, and III are useful in the treatment of plant infections caused bysuch fungi as Alternaria solani, and for treating B. subtilis infectedbreeding places of silkworms. These compounds also inhibit the growth ofM. phlei and K. pneumoniae, and inhibit the action of Newcastle diseasevirus on chick embryo cells. Tests with animals have also shown thesecompounds to have sedative and anorexigenic effects, and the compoundsare therefore useful for these purposes.

The novel 2-azabicyclo[3.2.2]non-6-ene-8,9-dicarbox- R2 (Iv) wherein R RR and R are as given above with a maleimide of the formula:

r") (V) wherein R is as given above.

The novel 2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximides of Formula IIare prepared by reacting a 1,3-dihydro-2H-azepiue of the formula:

N-CJH -Ra r H Ra (v1) wherein R R R R and n are as given above, with amaleimide of Formula V.

Maleimides of Formula V are either known in the art or can be preparedmy methods known in the art [e.g., U.S. Patents 2,444,536; 3,018,290;3,018,292; and Organic Syntheses, John Wiley & Sons, New York, vol. 41,page 93 (1961)].

1,3-dihydro-2H-azepines of Formulas IV and VI are novel in the art. Theycan be prepared by reacting the corresponding1,3-dihydro-2H-azepin-2-ones with lithium aluminum hydride, and thentreating the resulting reaction mixtures with water and a base accordingto the equa- In these equations, R R R R R and n are as given above.

l,3-dihydro-2H-azepin-2-ones of Formula VII wherein R R and R are asgiven above and wherein R is hydrogen are either known in the art or canbe prepared by the method known in the art, i.e., by interaction of thesodium salt of a di-ortho-substituted phenol with an ethereal solutionof chloramide (ClNH preferably in the presence of an excess of thephenol [Theilacker et al., Angew. Chem., 72, 131 (1960); ibid., 75,208-9 (1963)]. Phenols suitable for this reaction are known in the artor can be prepared by methods known in the art [e.g., U.S. Patents2,831,898; 2,841,622; 2,841,623; and 2,841,624; British Patents 717,588and 776,204; Kolka et al., J. Org. Chem. 22, 642-6 (1957); Stroh et al.,Angew. Chem. 69, 699-706 (1957)]. Examples of suitable phenols are2,6-dimethylphenol (2,6-Xylenol) 2,4,6-trimethylphenol (mesitol),2,6-diethylphenol,

2,4,6-triethylphenol, 2,6-dipropylphenol, 2,6-diisopropylphenol,2,4,6-triisopropylphenol, 2,6-diisobutylphenol,2,4,6-tri-tert-butylphenol, 2-ethyl-6-met-hylphenol,2-methyl-6-propylphenol, 2-ethyl-6-propylphenol,Z-tert-butyl-6-methylphenol, 2-sec-butyl-6-methylphenol,2-tert-butyl-6-ethylphenol, Z-tert-butyl-6-isopropylphenol,2-isobutyl-6-propylphenol, 4-sec-butyl-2,6-dimethylphenol,4-tert-butyl-Z,6-dirnethylphenol, 2,4-dimethyl-6-ethylphenol,2,4-dimethyl-6-propylphenol, 6-tert-butyl-2,4-dimethylphenol,2,6-diethyl-4-rnethylphenol, 2,6-diisopropyl-4-methylphenol,2,4-di-tert-butyl-6-methylphenol, 2,6-di-tert-butyl-4-ethylphenol,2,4-di-tert-butyl-6-propylphenol, 2,6-diisobutyl-4-propylphenol,2,6-di-tert-butyl-4-sec-butylphenol,2-tert-butyl-4-ethyl-6-methylphenol,2-sec-butyl-6-isopropyl-4-methylphenol,2-butyl-6-tert-butyl-4-methylphenol, and the like.

1,3-dihydro-ZH-azepin-Z-ones of Formula VII where in R is as given abovebut not hydrogen are prepared from the corresponding Formula VII1,3-dihydro-2H- azepin-2-ones wherein R is hydrogen by replacing saidhydrogen with the appropriate alkyl, alkenyl, alkynyl, cycloalkyl, oraralkyl moiety. Similarly, 1,3-dihydro- 2H-azepin-2-ones of Formula VIIIare prepared from the corresponding Formula VII 1,3-dihydro-2H-azepin-2-ones wherein R is hydrogen by replacing said hydrogen with the C,,H -Rmoiety. These N-substitutions are carried out in two steps according tothe equations:

In these equations, R R R R and n are as given above; the alkali metalreactant is a material selected from the group consisting of alkalimetals, alkali metal hydrides, and alkali metal amides; and RgX and X--CI-I -R are organic halides wherein X is selected from the groupconsisting of chloride, bromide, and iodide. R is selected from thegroup consisting of lower alkyl, alkenyl of 3 to 6 carbon atoms,inclusive, alkynyl of 3 to 6 carbon atoms, inclusive, cycloalkyl of 5 to10 carbon atoms, inclusive, and aralkyl of 7 to 11 carbon atoms,inclusive. It will be noted that this definition of R excludes hydrogenbut is otherwise the same as the above definition of R R and X areseparated by a chain of at least 2 carbon atoms, the nitrogen atom of Rbeing attached to a carbon atom of C H For the N-substitution of Formula1X 1,3-dihydro-2H- azepin-2-ones, suitable alkali metal reactants arelithium metal, sodium metal, potassium metal, lithium hydride, sodiumhydride, potassium hydride, lithium amide, sodium amide, and potassiumamide. Sodium metal, sodium hydride, and sodium amide are preferredbecause they are relatively inexpensive and of particularly suitable-reactivity for this purpose. The alkali metal, alkali metal hydride, oralkali metal amide is preferably used in a finely divided form,preferably in admixture with or as a suspension or dispersion in aninert liquid, for example, benzene, toluene, xylene, cumene, mesitylene,tetrahydronaphthalene, hexane, heptane, octane, mineral oil, dioxane,dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dialkylethers of ethylene glycol, dialkyl ethers of diethylene glycol, andmixtures thereof. Particularly preferred is an approximately 50 percentdispersion of micron-range sodium hydride crystals in mineral oil. Aninert liquid of the type mentioned above can also with advantage be usedas a solvent or diluent for the organic reactant, i.e., the Formula IX1,3-dihydro-ZI-I-azepin-Z-one,

The alkali metal reactant and the organic reactant are mixed, and thereaction between them is carried out at temperatures which can vary fromabout to about 150 C., preferably from about 25 to about 100 C. The 7most suitable temperature will of course depend upon such factors as thereactivities of the alkali metal reactant and the organic reactant, andthe nature of the solvent. For example, relatively high reactiontemperatures are usually necessary when using lithium reactants, andlower temperatures are preferred when using the more reactive materialssuch as potassium reactants. With the sodium reactants, for example,sodium hydride, reaction temperatures ranging from about 25 to about 100C. are preferred but higher or lower temperatures can be used. It ispreferred to react approximately equimolecular amounts of the organicreactant and the alkali metal reactant, although an excess of eitherreactant can be used. The time required for completing the reaction willdepend on the reaction temperature, the reactivities of the tworeactants, and the nature of the solvent. Illustratively, with sodiumhydride, the reaction frequently requires about minutes to about 3 hoursat temperatures ranging from about 50 -to about 100 C.

After the reaction between the alkali metal reactant and the organicreactant is complete, the metallo-organic reaction product can beisolated from the reaction mixture, for example, by removal of thesolvent by evaporation or distillation, and can be purified if desired,for example, by washing or digestion with a suitable solvent, forexample, additional portions of the reaction solvent. However, where thecharacter of the reaction mixture indicates the absence of a substantialamount of impurities, it is preferred to use the entire reaction mixturecontaining the metallo-organic reaction product in the next step of thereaction sequence which is a reaction with the organic halide of theformula R X or the formula XC H -R as above defined. It is preferredthat the R X halide be a bromide or an iodide, and that the XC H Rhalide be a chloride.

Examples of suitable R X bromides include methyl bromide, ethyl bromide,propyl bromide, isopropyl bromide, butyl bromide, sec-butyl bromide,isobutyl bromide, pentyl bromide, isopentyl bromide,

2-methylbutyl bromide, 1,2-dimethylpropyl bromide, l-ethylpropylbromide, l-methylbutyl bromide,

hexyl bromide,

isohexyl bromide, l-methylpentyl bromide, l-ethylbutyl bromide,Z-methylpentyl bromide, 1,2-dimethylbutyl bromide, allyl bromide,

Z-methylallyl bromide, 2-butneyl bromide,

3-butenyl bromide, 1,2-dimethylallyl bromide, Z-ethylallyl bromide,l-methyl-Z-butenyl bromide, 2-methyl-2-butenyl bromide,3-methyl-2-butenyl bromide, 2,3-dimethyl-2-butenyl bromide,1,3-dimethyl-2-butenyl bromide, 1-ethyl-2-butenyl bromide,4-methyl-2-pentenyl bromide, 2-propynyl bromide,

Z-butynyl bromide, 1-methyl-2-propynyl bromide, 3-butynyl bromide,

1-methyl-3 -butynyl bromide, 3-pentynyl bromide,

4-pentynyl bromide,

3-hexynyl bromide, Z-methyI-B-pentynyl bromide, cyclopentyl bromide,cyclohexyl bromide, Z-methylcyclopentyl bromide, Z-methylcyclohexylbromide, 3-methylcyclohexyl bromide, 4-methylcyclohexyl bromide,Z-ethylcyclopentyl bromide, 3-ethylcyclopentyl bromide,4-ethylcyclohexyl bromide, 3-isopropylcyclopentyl bromide,2,3-dimethylcyclohexyl bromide, cycloheptyl bromide, cyclooctyl bromide,4-tert-butylcyclohexyl bromide, cyclonoyl bromide,

cyclodecyl bromide,

benzyl bromide,

phenethyl bromide, 2-phenylpropyl bromide, 3-phenylpropyl bromide,4-phenylbutyl bromide, l-naphthylmethyl bromide, 2-naphtl1ylmethylbromide, and the like.

Suitable R X chlorides and iodides include those corresponding to theabove bromides. These halides are either known in the art or can beprepared by methods known in the art, for example, by reaction of thecorresponding alcohol with a phosphorus halide, by halogenation of asuitable saturated hydrocarbon, or by addition of a hydrogen halide to asuitable unsaturated hydrocarbon.

Examples of suitable XC,,H ,,R chlorides are N- 2-chloroethyldimethylamine,

N-( 2-chloroethyl -N-methylethylamine, N- 2-chloroethyl diethylamine,

N- 2-chloroethyl dipropylamine,

N- 2-chloroethyl diisopropylamine,

N- 2-chloroethyl -N-methylisopropylamine, N- (2-chloroethyldibutylamine,

N- 2-chloroethyl di-sec-butylamine,

N- 2-chloroethyl diisobutylamine,

N- 2-chloroethyl di-tert-butylamine,

N- (2-ch1oroethyl) -N-methylbutylamine, N- (2-chloroethyl)-N-ethyl-sec-butylamine,

N- 2-chloroethyl) dipentylamine,

N- (2-chloroethyl) diisopentylamine,

N- 2-chloroethyl) -N-methylpentyl amine,

N- (2-chloroethyl -N-ethyl-2-methylbutyl amine,

N- (2-chloroet-hyl dihexylamine,

N- 2-chloroethyl diisohexylamine,

N- 2-chloroethyl -N-methylhexylamine,

N- (2-chloroethyl) -N-ethyl-2, 3 -dimethylbu tyl am ine,

N- 3-chloropropyl dimet-hylamine,

N- 3 -chlor opropyl diethylamine,

N- 3 -chloropropyl) -N-methylis obutylamine,

N- 3-chloropropyl diisopentylamine,

N- 2-chloro pro pyl )diethyl amine,

N- 2-chloropropyl) -N-methylis opropylamine,

N- (4-chlorobutyl dimethylamine,

N- (4-chlo robutyl) di-tert-butyl amine,

N- 3-chlorobutyl -N-methylethylamine,

N-(3-chloro-1-methylpropyl)dibutylamine,

N-(2-chloro-1-methylpropyl) diethyl-amine,

N- -c'hloropentyl dimethylamine,

N(3-chloro-1,Z-dimethylpropyl)dipropylamine,

N- (5 -chloro -2-methylpentyl diethylamine,

N( 6-chlorohexyl )dihexylamine,

N-(4-chloro-1-methylpentyl) -N-methylethyl amine,

N-(Z-chloroethyl aziridine,

N- (Z-chloroethyl -2-methylaziridine,

N- 3 -chloropropyl -2,3 -dimethylaziridine,

N- 4-chlorobutyl) -2,2-'dimethylaziridine,

N- (5 -chloro-2-rnethylpentyl) aziridine,

N- 2-chloroethyl azetidine,

N- (Z-chloroethyl -2-methylazetidine,

N- 3 -chloropropyl -3 -me thylazetidine,

N- 2-chloro pro pyl) -2-octylazetidine,

N (5 -chloropentyl) -2-2-dime thylazetidine,

N- (5-chloro-2-methylpentyl -3 ,3-diethylazetidine,

N-(3-chloro-1,2-dimethylpropyl) 2-,4,4-tri-methylazetidine,

N- (2-chloroet-hyl) -pyrrolidine,

N- (3-chloropropyl) -2-methylpyrrolidine,

N- 2-chloro pro py-l) 3 -butylpyrrolidine,

N- (4-chlorobuty1) -2-isohexylpyrrolidine,

N- (-2-chloroethyl) -2, 3 -dimethylpyrrolidine,

N- (Z-chloroethyl) -2,2,4-trime thylpyrrolidine,

N (3 -chloro-1methylpropyl) -2,Z-dimethylpyrrolidine,

N- (6-chlorohexyl) -2,5 -diethylpyrrolidine,

N 3-chlorobutyl) -3-tert-butylpyrrolidine,

N- 5 -chloro-2-methylpentyl) -3,4-dioctylpyrrolidine,

N 3-chloropropyl) piperidine,

N (2-chloroethyl) -2-methylpiperidine,

N (2-chloropropyl) -3-methylpiperidine,

N- 3 -chlorobutyl) -4-methylpiperidine,

N- (-4-chlorobutyl -3 -is opropylpiperidine N- (2-chloro-1-met-hylethyl)-4-tert-butylpiperidine,

N-(Z-chloroethyl -2,4,6-trimethylpiperdine,

N- 3-chloropropyl -2-methyl-5 -ethylpiperidine,

N- S-chloropentyl) -3,5-dipentylpiperidine,

N 6-chlorohexyl) -2,6-dimethyl-4-octylpiperidine,

N- (2-chloroethyl) hexyhydroazepine,

N- (2-chlorobutyl -2-ethylhexahydroazepine,

N- 3-chloropropyl) -4-tert-butylhexahydroazepine,

N- 3-chloro-1-methylpropyl) -3,3-dimethylhexahydroazepine,

N- (5-c-hloropentyl) -2,4,6-tripropylhexahydroaze pine,

N- ('2-chloroethyl) heptamethylenimine,

N- 3 -chloropropyl) -2-me thylheptamethylenimine,

N- 3-chlorobutyl) -2,4-diisopropylheptamethylenimine,

N(5-chloro-2-methylpentyl) -3,3-dimethylheptamethylenimine,

N- (4-chlorobutyl) octamethylenimine,

N- (2-chloroethyl) -3-methyloctamethylenimine,

N 6-chlorohexyl) -4-isoooctyloct amethylenimine,

N- 3-chloropropyl morpholine,

' N- (3-chloro-1-methylpropyl) -2-ethylmorpholine,

10 N- 2-chloroethyl)-2-methyl-5-ethylmorpholine, N(4-chloro-l-methylpentyl)-3,3-d-imethylmorpholine,N-(Z-chloropropyl)thiomorpholine, N 5 -chlorohexyl)-3-methylthiomorpholine, N- (2-chlor0ethyl) -2,2-dipentylthiomorpholine,

and the like. Examples of X-C,,H R bromides and iodides suitable forthis reaction are the bromides and iodides corresponding to each of theabove chlorides.

These XC,,H ,,R organic halides are either known in the art or can beprepared by methods known in the art [e.-g., US. Patents 2,483,998;2,584,131; 2,590,125; and 2,608,574; I. Am. Chem. Soc., 68, 1516-23(1946); I. Am. Chem. Soc., 68, 1556-9 (1946); I. Am Chem. Soc., 68,1579-84 (1946); J. Am. Chem. Soc., 68, 2592-2600 (1946); I. Am. Chem.Soc., 69, 1258-60 (1947); I. Am. Chem. Soc., 70, 3100-2 (1948); J. Am.Chem. Soc., 71, 3988-90 (1949); J. Am. Chem. Soc., 74, 653-6 (1952); J.Am. Chem. Soc., 75, 2072-4 (1953); J. Am. Chem. Soc., 77, 2855-60(1955); and Helv. Chim. Acta., 37, 472-83 (1954)].

Either type of organic halide is added to the metalloorganic reactionmixture either dropwise or in larger portions. Alternatively, themetallo-organic reaction mixture can be added in a similar manner to theorganic halide. In either case, the organic halide can be dissolved in asuitable inert solvent, preferably in one or more of the solventsalready present in the metalloorganic reaction mixture or describedabove as being useful in its preparation. It is particularlyadvantageous to use a solvent for this purpose when the organic halideis a solid at room temperature. Although only one molecular equivalentof the organic halide is required for reaction with one molecularequivalent of the metalloorganic reaction product (preferably calculatedon the basis of the amount of 1,3-dihydro-2H-azepin-2-one used toprepare the latter), it is preferred to use an excess of the organichalide, for example, about 1.01 to about 5 or even more molecularequivalents of the halide per molecular equivalent of themetallo-organic reaction product. Particularly preferred is the use ofabout 1.05 to about 2 molecular equivalents of organic halide permolecular equivalent of met-allo-organic reaction product. Suitablereaction times and reaction temperatures for the interaction of organichalide and metallo-organic reaction product depend upon the nature ofthe reactants and the solvent, and the usual inverse relationshipbetween time and temperature is observed. Suitable reaction temperaturesrange from about 0 to about 200 C., preferably from about 10 to about C.Usually, reaction temperatures ranging from about 25 to about 75 C. andreaction times ranging from about 1 to about 20 hours are satisfactory.Before starting the mixing of the metallo-organic reaction mixture andthe organic halide, it is desirable to cool the former, for example,externally with ice, to within a range of about 0 to about 25 C.,preferably to Within a range of about 5 to about 15 C. After the mixingis complete, the temperature of the reaction mixture is caused to riseto a suitable reaction temperature as discussed above. The desired1,3-dihydro- 2H-azepin-2-one of Formula VIII or Formula X can beisolated from the reaction mixture by conventional methods, for example,by removal of reaction solvent by evaporation or distillation. If analkali metal halide is present as a solid in the reaction mixture, itmay with advantage be removed by filtration before the desired organicreaction product is isolated.

In the reaction of lithium aluminum hydride with 1,3-dihydro-2H-azepin-2-ones, the stoichiometric amounts of of reactantscorrespond to 0.75 mole of lithium aluminum hydride and one mole of aFormula IX 1,3-dihydro-2H- azepin-2-one, and to 0.5 mole of lithiumaluminum hydride and one mole of a Formula VIII or Formula X (FormulaVII wherein R is not hydrogen) 1,3-dihydro- 2H-azepin-2-one. However, itis preferred to use an excess of the lithium aluminum hydride,advantageously about 50 to about 300 percent excess. A larger excess canbe used but there is little if any advantage in doing so.

The reaction between lithium aluminum hydride and1,3-dihydro-2H-azepin-2-one is preferably carried out by adding adiethyl other solution of the latter reactant to a slurry of the lithiumaluminum hydride in diethyl ether, and then refluxing the resultingreaction mixture for about one to about hours, the optimum time beingdependent on the nature of the organic reactant It is important toexclude oxygen from the reaction mixture. This can be accomplished bypassing a slow stream of an inert gas, for example, nitrogen or helium,through the reaction vessel during the reflux period. It is alsoimportant to exelude substantial amounts of moisture from the reactionmixture. The use of dry solvents, reactants, and reaction vessels ispreferred.

The first step in the isolation of the desired reaction product from thefinal lithium aluminum hydride reaction mixture involves addition ofwater and a base, preferably an alkali metal hydroxide such as sodiumhydroxide, to the reaction mixture. 1,3-dihydro-2H-azepines tend todecompose in the presence of substantial amounts of water, and it ispreferred generally to use the minimum amount of water for this step. Itis usually preferred to cool the final reaction mixture externally withice, and then to add with stirring successively about 1 ml. of Water,about 1 ml. of percent aqueous sodium hydroxide solution, and about 3ml. of water for each gram of lithium aluminum hydride originally usedin the reaction mixture. When these amounts of water and sodiumhydroxide solution are used, the aluminate salts usually precipitate inthe form of a granular solid with no separate aqueous phase. The solidprecipitate is readily separated from the organic solution by filtrationor centrifugation. The free base form of the desired organic product canthen be isolated by evaporation of the solvent.

1,3-dihydro-2H-azepines of Formula IV wherein R is hydrogen are usuallysolids, and can be purified by recrystallization or precipitation from asuitable solvent or mixture of solvents. 1,3-dihydro-2H-azepines ofFormula IV wherein R is as given above but not hydrogen, or of FormulaVI are usually liquids, and usually can be purified by distillation atreduced pressure. Alternative methods of purification for either type of1,3dihydro-2H- azepine are partition between the phases of a nonaqueoustwo-phase solvent system or chromatography. Frequently, however, thelithium aluminum hydride reaction produces 1,3-dihydro-2H-azepines ofsufiicient purity that a purification step is unnecessary beforesubsequent reaction with the Formula V maleimide. Indeed, the novel1,3-dihydro-ZH-azepine intermediate of this invention tend to be lessstable to air and moisture than other organic compounds, and it isusually advantageous to prepare them shortly before transformation tothe desired 2-azabicyclo [3.2.2]non-6-ene-8,9-dicarboximides of FormulaI or II, and to minimize exposure to air and moisture.

The reaction between a Formula V or Formula VI 1,3- dihydro-ZH-azepineand a maleimide of Formula V is carried out by mixing these tworeactants. Ordinarily, it is preferred to react approximatelyequimolecular amounts of the two reactants to avoid the necessity ofsubsequent separation of the excess reactant from the desired adduct ofFormula I or Formula II. However, an excess of either reactant can beused, for example, about 1.1 to about 3 or even more molecularequivalents of one reactant per molecular equivalent of the otherreactant, and in some cases, such an excess is advantageous, especiallywhen the reaction is slow and the yield of desired product relativelysmall when equimolecular amounts of reactants are used. Usually,however, the reaction rate and yield of adduct are high enough so thatthere is no advantage in using an excess of either reactant. Although itis not essential to use a reaction solvent, especially when the FormulaIV or Formula VI reactant is a liquid within the preferred reactiontemperature range, it is preferred that a solvent be present in thereaction mixture. Suitable solvents include normally liquid aromatichydrocarbons, e.g., benzene, toluene, xylene, and cumene; ethers, e.g.,diethyl ether, tetrahydrofuran, and dioxane; and such solvents aschlorobenzene, tetrahydronaphthalene, and cyclohexane. Two criteria fora suitable solvent are that both reactants be moderately soluble thereinand that the solvent not react with either reactant.

The reaction between the Formula V maleimide and the Formula IV orFormula VI 1,3-dihydro-2H-azepine is usually exothermic. It is preferredto add a solution of the 1,3-dihydro-2H-azepine rapidly to a solution ofthe maleimide, keeping the resulting mixture in the range about 10 toabout 35 C. with external cooling if necessary. The initial color of thereaction mixture is usually red. This color then gradually fades to apale shade of yellow or orange as the reaction proceeds. After theaddition is complete, the mixture is allowed to stand or is stirred inthe range about 0 to about C. until the desired reaction is complete.Usually the reaction proceeds at a satisfactory rate in the range about10 to about 50 C. At lower temperatures, the reaction rate tends to beinconveniently slow. At higher temperatures, the yield of the desiredFormula I or Formula II product tends to be lower than within thepreferred reaction temperature range.

The time required for completion of the reaction will vary according tosuch factors as the reactivitie of the two reactants, the reactiontemperature, and the nature of the reaction solvent. The usual inverserelationship between reaction time and reaction temperature is observed.At about 25 C., the reaction usually requires from about one-half toabout 36 hours.

After the reaction between the maleimide and the 1,3- dihydro-ZH-azepineis complete, the Formula I or Formula II product can be isolated byconventional techniques, for example, by evaporation of the solventunder reduced pressure. Formula I products are usually solids at normaltemperature. The Formula II products can be solids or liquids. Thesolids can be purified by recrystallization from a suitable solvent ormixture of solvents. The liquids can be purified by reduced pressuredistillation. Chromatography is also a useful technique for purificationof these products.

The free base form of a Formula I or a Formula II 2-azabicyclo[3.2.2]n0n-6-ene-8,9-dicarboximide is produced by the abovereaction between the maleimide and the l,3-dihydro-2H-azepine. TheFormula I free bases can be transformed to monoacid addition salts andthe Formula II free bases to either monoor diacid addition salts byneutralization with the appropriate amount of the correspondinginorganic or organic acid, examples of which are given above. Thesetransformations can be carried out by a variety of procedures known tothe art to be generally useful for the preparation of amine acidaddition salts. The choice of the most suitable procedure will depend ona variety of factors including convenience of operation, economicconsiderations, and particularly the solubility characteristics of theFormula I or Formula II amine, the acid, and the acid addition salt. Ifthe acid is soluble in water, the basic compound of Formula I or FormulaII can be dissolved in Water containing an equivalent amount of theacid, and thereafter, the water can be removed by evaporation. If theacid is soluble in a relatively non-polar solvent, for example, diethylether or diisopropyl ether, separate solutions of the acid and theFormula I or Formula II compound in such a solvent can be mixed inequivalent amounts, whereupon the monoacid addition salt will usuallyprecipitate because of its relatively low solubility in the non-polarsolvent. Alternatively, the basic Formula I or Formula II compound canbe mixed with an equivalent amount of the acid in the presence of asolvent of moderate polarity, for example, a lower 'alkanol, a loweralkanone, or a lower alkyl ester of a lower alkanoic acid. Examples ofthese solvents are ethanol, acetone, and ethyl acetate, respectively.Subsequent admixture of the resulting solution of acid addition saltwith a solvent of relatively low polarity, for example, diethyl ether orhexane, will usually cause precipitation of the monoacid addition salt.When it is desired to prepare a diacid addition salt of a Formula IIfree base, at least two equivalents of acid is used in one of the aboveprocedures rather than the one equivalent specified above. The acidaddition salt is usually a solid and can be purified byrecrystallization from a suitable solvent or mixture of solvents. Theacid addition salt can be transformed back to the free base by treatmentwith a base, e.g., sodium hydroxide. In some instances, the Formula I orFormula II compound is more easily purified in acid addition salt formthan in free base form. Transformation back to the free base form thuscompletes a means of obtaining a particularly pure free base.

The novel 2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximides of Formula IIIare prepared by reacting the corresponding Formula I2-azabi-cyclo[3.2.2]non-6-ene-8,9- dicarboximide, wherein R is hydrogen,with a carboxylic acid anhydride of the formula:

wherein R is selected from the group consisting of hydrogen and alkyl of1 to 4 carbon atoms, inclusive, and wherein R is alkyl of 1 to 4 carbonatoms, inclusive. When R of the desired Formula III product is alkyl, Rand R of the Formula XI anhydride should be alike. If R is a differentalkyl than R a mixture of Formula III products will be produced, becausepart of the R7 alkyl moieties therein will originate in R of theanhydride, and part in R of the anhydride. When R of the desired FormulaIII product is hydrogen, R of the anhydride should be hydrogen. In thatevent, it is preferred that R be methyl. A Formula III product wherein Ris hydrogen is the main product, and in some instances the exclusiveproduct, of the interaction of the Formula I reactant and this mixedanhydride of formic and acetic acid.

Anhydrides of Formula XI are known in the art. With particular regard tothe anhydride wherein R is hydrogen and R is methyl, see Huffman, J.Org. Chem., 23, 727-9 (1958).

The transformation of the Formula I reactant (R is hydrogen) to theFormula III product is carried out by mixing the Formula I reactant withat least an equimolecular amount of the Formula XI anhydride and heatinguntil no further reaction takes place. An inert reaction solvent, forexample, benzene or diethyl ether, can be added, but it is preferredthat an excess of the anhydride be used as the diluent. Satisfactoryresults are usually obtained by use of about 10 to about 30 moles ofanhydride per mole of Formula I reactant. The mixture is heated,preferably in the range about 35 to about 125 C. for about one to about24 hours. Satisfactory results are usually obtained with Formula XIanhydrides wherein R and R are both alkyl by heating at about 100 C. forabout 1 to about hours. Lower reaction temperatures, for example about35 to about 60 C. are preferred when R in the anhydride is hydrogen.

The desired Formula III product can be isolated from the reactionmixture by conventional techniques, for example, by removal of excessanhydride by distillation at reduced pressure. It is often sufficientmerely to cool the reaction mixture, for example to the range about toabout 25 C. whereupon the desired Formula III product will precipitate.It is preferred to protect the reaction mixture from atmosphericmoisture during the heating and isolation stages. The isolated FormulaIII product can be purified, if desired, by conventional techniques, forexample, by recrystallization from a suitable solvent or mixture ofsolvents, or by chromatography.

The invention can be more fully understood by the following examples.

EXAMPLE 1 1,3-dihydr0-3,5,7-trimethyZ-ZH-azepin-Z-one Following theprocedure of Theilacker et a1, supra, the sodium salt of2,4,6-trimethylphenol was reacted with chloramide in the presence of anexcess of this phenol. 1,3-dihydro-3,5,7-trimethyl-2H-azepin-2-one wasobtained; M.P. 132 C.

Following the procedure of Example 1 but substituting for the2,4,6-trimethylphenol,

2,6-dimethylphenol; 2,6-diethylphenol; 2,6-dipropylphenol;2,6-diisopropylphenol; 2,6-diisobutylphenol; 2,6-dibutylphenol;2,4,6-triethylphenol; 2,6-diethyl-4-methylphenol;2,6-dimethy1-4-ethylphenol; 4-tert-butyl-2,G-dimethylphenol;2,6-diisopropyl-4-methylphenol; 2,6-diisobutyl-4-propylphenol;4-sec-butyl-2,6-dimethylphenol; and 2,4,6-triisopropylphenol,

there are obtained 1,3-dihydro-3,7-dimethyl-2H-azepin-Z-one;1,3-dihydro-3,7-diethyI-ZH-azepin-Z-one;1,3-dihydro-3,7-dipropyl-2H-azepin-2-one;1,3-di-hydr-o-3,7-diisopropyl-ZH-azepin-Z-one;1,3-dihydro-3,7-diisobutyl-2H-azepin-2-one;1,3-dihydro-3,7-dibutyl-2H-azepin-2-one;1,3-dihydro-3,5,7-triethyl-2H-azepin-2-one;1,3-dihydro-3,7-diethyl-S-methyl-ZH-azepin-Z-one;1,3-dihydro-3,7-dimethyl-5-ethyl2H-azepin-2-one;1,3-dihydro-5-tert-butyl-3,7-dimethyl-2H-azepin-2-one; 1,3-dihydro-3,7-diisopropyl-5-methyl-2H-azepin-2-one;1,3-dihydro-3,7-diisobutyl-5 propyl-2H-azepin-2one;l,3-dihydro-5-sec-butyl-3,7-dimethyl-2H-azepin-2-one;

and 1,3-dihydro-3,5,7-triisopropyl-2H-azepin-Z-one,

respectively.

EXAMPLE 2 1,3-dihydro-1,3,5,7-tetramethyl-ZH-azepin-Z-one A 51.5% sodiumhydride suspension in mineral oil (9.0 g.; equivalent to 0.19 mole ofsodium hydride) was added to a solution of1,3-dihydro-3,5,7-trimethyl-2H- azepin-Z-one (29.0 g.; 0.19 mole) in 150ml. of dimethylformamide. The mixture was stirred at 50 C. for 1 hour.After cooling, methyl iodide (42.6 g.; 0.30 mole) was added in twoportions. After stirring for 1 hour, 250 ml. of diethyl ether was addedand the resulting slurry was filtered. The oil remaining afterevaporation of the solvent in the filtrate was distilled to yield 29.45g. of a colorless liquid; B.P. -120" C. at 11 mm. Redistillation gave1,3-dihydr-o-1,3,5,7-tetramethyl-ZH-azepin-Z- one; B.P. 121.5 C. at 13mm.; n 1.5198.

Analysis.-Calcd. for C H NO: C, 72.69; H, 9.15; N, 8.48. Found: C,72.32; H, 9.26; N, 8.59.

Following the procedure of Example 2 but substituting for the methyliodide, isopropyl chloride; propyl iodide; isobutyl bromide; pentylbromide; hexyl chloride; allyl bromide; 2-methyl-2-butenyl bromide;4-methyl-2-pentenyl chloride; 2-propynyl bromide; 3-pentynyl chloride;cyclopentyl chloride; cyclohexyl bromide; 4-tert-butylcyclohexylchloride, benzyl bromide; and l-naphthylmethyl chloride, there areobtained 1,3-dihydro-1-isopr-opyl-3,5,7-trimethyl-2H-azepin-2-one;1,3-dihydro-1- propyl-3,5,7-trimethyl-2H-azepin-2-one;1,3-dihydrol-isobutyl-3,5,7-trimethyl-2H-azepin-2-one;

1 1,3-dihydro-l-pentyl-3,5,7-trimethyl-2H-azepin-Z-one;1,3-dihydro-1-hexyl-3,5,7-trimethyI-ZH-azepin-Z-one;1,3-dihydro-1-allyl-3 ,5 ,7-trimethyl-2H-azepin-2-one;1,34lihydro-l-(2-rnethyl-2-butenyl)-3,S,7-trimethyl-2H- aZepin-Z-one;

1,3-dihydro-1-(4-methyl-2-pentenyl) -3,5,7-trimethyl-2H- azepin-Z-one;

1,S-dihydro-1-(2-propynyl) -3,5,7-trimethyl-2H-azepin-2- one;

1,3-dihydrol 3 -pentynyl -3 ,5 ,7-trimethyl-2H-azepin-2- one;

1,3-dihydro-1-cyclo-pentyl-3,5,7-trimethyl-2H-azepin-2- one;

1,3-dihydrol-cyclo-hexyl-3,5,7-trimethyl-2H-azepin-2- one;

1,3-dihydro-l-(4-tert-butylcyclohexyl)-3,5,7-trimethyl- 2H-azepin-2-one;

1,3-dihydro-1-benzyl-3 ,5 ,7-trimethyl-ZH-azepin-Z-one;

and

1,3-dihydro-l -(1-naphthylmethyl)-3,5,7-trimethyl-2H- azepin-Z-one,

respectively.

Following the procedure of Example 2 but substituting for thecombination of 1,3-dihydro-3,5,7-trimethyl-2H- azepin-Z-one and methyliodide as reactants,

1,3-dil1ydro-3,7-dimethyl-2H-azepin-2-one plus isopropyl chloride;

1,3-dihydro-3,7-dimethyl-2I-I-azepin-2-one plus cycl-opentyl chloride;

1,3-dihydro-3,7-diethyl-2H-azepin-2-one plus benzyl bromide;

1,3-dihydro-3,7-diethyl-2H-azepin-2-one plus allyl bromide;

1,3-dihydro-3,7-dipropyl-ZH-azepin-Z-one plus propyl iodide;

1,3-dihydro-3,7-diisopropyl-ZH-azepin-Z-one plus 4-tertbutylcyclohexylchloride;

1,3-dihydro-3,7-diisobutyl-2H-azepin-2-one plus propyl bromide;

1,3-dihydro-3,7-dibutyl-2H-azepin-2-one plus pentyl brornide;

1,3-dihyd1o-3,5,7-triethyl-ZH-azepin-Z-one plus 2- propynyl bromide;

1,3-dihydro-3,7-diethyl-5-methyl-2H-azepin-Z-one plus benzyl bromide;

1,3-dihydro-3,7-dimethyl-5-ethyl-2H-aZepin-2-one plus hexyl chloride;

1,3-dihydro-5-tert-butyl-3,7-dimethyl-ZH-azepin-Z-one plusl-naphthylmethyl chloride;

1,3-dihydro-3,7-diisopropyl-5-methyl-2H-azepin-2-one plus allyl bromide;

1,3-dihydro-3,7-diisobutyl-5-propyl-2H-azepin-2-one plus propyl iodide;

1,3-dihydro-5-sec-butyl-3,7-dimethyl-2H-azepin-2-one plus 2-propynylbromide; and

l,3-dihydro-3,5,7-triisopropyl-ZH-azepin-Z-one plus isopropyl chloride,

there are obtained 1,3-dihydro-3,7-dimethyl-1-isopropyl-2H-azepin-2-one;1,3-dihydro-1-cyclopentyl-3,7-dimethyl-2H-azepin-2-one;1,3-dihydro-lbenzyl-3,7-diethyl-ZI-I-azepin-Z-one;1,3-dihydro-1-allyl-3,7-diethyl-2H-azepin-2-one;1,3-dihydro-1,3,7-tripropyl-2H-azepin-2-one; 1,3 -dihydro-1-(4-tert-butylcyclohexyl) -3,7-diisopropyl- ZH-azepin-Z-one;1,3-dihydro-3 ,7-diisobuty1-1-propyl-2H-azepin-2-one;1,3-dihydro-3,7-dibutyl-l-pentyl-2H-azepin-2-one;1,3-dihydro-l-(2-propynyl)-3,5,7-triethyl-2H-azepin- 2-one;1,3-dihydro-1-benzyl-3,7-diethyl-5-methyl-2H-azepin- 2-0ne;1,3-dihydro-3,7-diinethy1-5-ethyl-l-hexyl-2H-azepin- 2-one;

1 n 1 O 1,3-dihydro-5 -tert-butyl-3 ,7-dimethyl-1-( l-naphthylmethy l-2H-azepin-2-one; 1,3-dihydro-1-allyl-3,7-diisopropyl-5-1nethyl-2H-azepin- 2-one;1,3-dihydro-3,7-diisobutyl-1,5-dipropyl-2H-azepin- 2-one;1,3-dihydro-5-sec-butyl-3,7-dimethyl-1-(2-propynyl)- ZH-azepin-Z-one;and 1,3-dihydro-1,3,5,7-tetraisopropy1-2H-azepin-2-one,

respectively.

EXAMPLE 3 1,3-dihydr0-1-(2-diethylaminoethyl)\-3,5,7-trimethyl-ZH-azepin-Z-one A 51.5% sodium hydride suspension in mineral oil (2.33g.; equivalent to 0.05 mole of sodium hydride) was added to a solutionof 1,3-dihydro-3,5,7-trimethyl-2H-azepin-2 one (7.6 g.; 0.05 mole) in 50ml. of dimethylformamide. The mixture was stirred at 50 C. for 1 hour.After cooling to 5-l0 C., a solution of N-(2-chloroethyl)diethylamine(7.05 g.; 0.052 mole) in 10 ml. of xylene was added. After stirring atabout 25 C. for 1.5 hours, ml. of diethyl ether was added and theresulting slurry was filtered. The residue remaining after evaporationof the solvent in the filtrate was distilled to yield 10.8 g. of1,3-dihydro-1-(Z-diethylaminoethyl)-3,5,7-trimethyl- 2H-azepin-2-one asa very pale yellow liquid; B.P. 123 C. at 0.3 mm; 11 1.5002.

EXAMPLE 4 1,3-dihya'r0-1- (3-dimethylaminopropyl) -3,5,7-trimcthyl-ZH-azepin-Z-one The procedure of Example 3 was followed except that inplace of N-(2-chloroethyl)diethylamine, there was used N-(3-chloropropyl)dimethylamine (6.1 g.; 0.05 mole). There was obtained 2.50 g.of l,3-dihydro-1-(3-dimethy1-aminopropyl)-3,5,7-trimethyl-ZH-azepin-Z-one as a pale yellow liquid;B.P. 121-127 C. at 0.3 mm.

Following the procedure of Example 3 but substituting for theN-(2-chloroethyl)diethylamine,

N- 2-bromoethyl dimethyl amine;

N- 2-iodoethyl diisopropylamine;

N- 2-chloroethyl -N-ethyl-2-methylbutylamine; N- 2-chloroethyldipentylamine;

N- 3-brornopropyl diet-hylami no;

N- 3-bromopropyl -N-methylpentylamine N- 3-chloropropyl dibutylamine;N-(2-iodopropy1)-N-methylisopropylamine;

N- 3-bromobutyl -N-methylbutylamine N- S-bromopentyl dimethylamine;

N- 6-chlorohexyl dihexylamine;N-(3-iodo-1,2-dimethylpropyl)dibutylamine; and N- 4-chlorol-methylpentyl -N-methylethylamine,

there are obtained 1,3-dihydro- 1 Z-dimethylaminocthyl -3,5 ,7-trimethy1- 2I-I-azepin-2-one;

1,3-dihydro-1-(2-diisopropylaminoethyl)-3 ,5,7-trimethyl-2H-azepin-2-one;

1,3-dihydro-1-[2-(N-ethyl-Z-methylbutylamino)-ethyl]- 3 ,5,7-trimethyl-ZH-azepin-Z-one;

1,3-dihydrol- [2-( dipentylamino ethyl] -3 ,5 ,7-trimethyl-2H-azepin-2-one;

1,3-dihydro- 1- 3-diethylaminopropyl) -3 ,5 ,7-trimethyl-2H-azepin-2-one;

1 ,3-dihydro-1- [3 (N-methylpenthylamino propyl] -3 ,5 ,7-

trimethyl-ZH-azepin-Z-one;

1,3-dihydro- 1 3- dibutylamino propyl] -3,5,7-trimethyl-2H-azepin-2-one;

1,3-dihydro- 1- 1-methyl-2- N-methylisopropyl amino) ethyl]-3,5,7-itrimethyl-2H-azepin-2-one;

1,3-dihydro-1-[1-methyl-3-(N-methylbutylamino)propyl] -3,5,7-trimethyl-2I-I-azepin-2- one .1 7 1,3-dihydro-1-(-dimethylaminopentyl)-3,5 ,7-trimethy1- ZH-azepin-Z-one;1,3-dihydro-1-(6-dihexylaminohexyl)-3,5,7-trimethyl- 2H-azepin-2-one;1,3-dihydro-1-[3-(N-methylpentylamino)propyl] -3,5,7-

trimethyI-ZH-azepin-Z-one; and1,3-dihydro-1-[1-methyl-4-(N-methylethylamino)pentyl]- 3,5 ,7-trimethyl-2H-azepin-2-one, respectively.

Following the procedure of Example 3 but substituting for thecombination of 1,3-dihydro3,5 ,7 -trimethyl-2H-azepin-2-one andN-(2-chloroethyl)diethylamine as reactants,

there are obtained 1,3 -dihydro-1- (Z-dimethylaminoethyl) -3,7-dimethyl-2H- azepin-Z-one;

1, 3 -dihydro- 1- (2-dip ropyl amino ethyl) -3 ,7-dimethyl-2H-azepin-Z-one;

1,3-dihydrol- (Z-dipentylaminoethyl) -3 ,7-diethyl-2H- azepin-2-one;

1,3-dihydro-1- 3-diisopropylaminopropyl) -3,7-dipropyl- 2H-azepin-2-one;

1,3-dihydro-1- 3-dibutylaminobutyl) -3,7-diisobutyl 2H-azepin-2-one;

1,3-dihydro-1-( 1-methyl-2-dibutylaminopropyl) -3 ,7-

dibutyl-2H-azepin-2-one;

1,3-dihydro-1-( 5 -dimethylaminopentyl) -3,5,7-triethyl-2H-azepin-2-one;

1,3-dihydro-1- 6-dihexylaminohexyl) -3,7-diethyl-5-methyl-2H-azepin-2-one;

1, 3 -dihydro-1- 1-methyl-4- (N-methylethylamino) pentyl]-3,7-dimethyl-5-ethyl-2H-azepin-2-one;

1,3-dihydro-1- (Z-diethylaminoethyl) -3,7-diisopropyl-5-methyl-2H-azepin-2-one; and

1,3-dihydro-1-(2-diisopropylaminoethyl)-3,5,7-triisopropyl-2H-azepin-2-one,

respectively.

EXAMPLE 5 1,3-dihydr0-1-[2-(1-pyrr0lidinyl) ethyl] -3,5,7-trimethyI-ZH-azepin-Z-one A 51.5% sodium hydride suspension in mineraloil (4.65 g.; equivalent to 0.10 mole of sodium hydride) was added inseveral portions to a solution of 1,3-dihydro-3,5,7-trimethyl-2H-azepin-2-one (15.1 g.; 0.10 mole) in 100 ml. ofdimethylformamide. The mixture was stirred at 55 C. for 30 minutes.After cooling to 10 C., a solution of N-(Z-chloroet-hyl)pyrrolidine inan equal weight of toluene (32 g. of solution; equivalent to 0.12 moleof halide) was added in a thin stream, the resulting mixture being keptbelow 20 C. by external cooling.

18 When the addition was complete, the mixture was stirred for anadditional 1.5 hours at 25 C. Diethyl ether (about 200 ml.) was thenadded and the resulting slurry was filtered. The residue remaining afterevaporation of the solvent in the filtrate was distilled to yield 18.2g. of 1,3-dihydro-1- [2-( l-pyrrolidinyl) ethyl] -3,5 ,7-trimethyl-2H-azepin-2-one; B.P. 126138 C. at 0.13 mm.; n 1.6693.

EXAMPLE 6 1,3-dihya'ro-1- [2- (2,2,4-trimethyl-1-pyrr0lidinyl) ethyl]-3,5,7-trimethyl-2H-azepin-2-one The procedure of Example 5 was followedexcept that in place of N-(2-chloroethyl)pyrrolidine, there was usedN-(2-chl0r0ethyl)-2,2,4-trimethylpyrrolidine (42.2 g. of a 50% toluenesolution; equivalent to 0.12 mole of halide). There was obtained 26.7 g.of 1,3-dihydro-1-[2-(2,2,4- trimethyl 1 pyrrolidinyl)ethyl] 3,5,7trimethyl 2H- azepin-Z-one; B.P. 136147 C. at 0.2 mm.; n 1.5034; B.P. onredistillation C. at 0.5 mm.; n 1.5040.

EXAMPLE 7 1,3-dihydr0-1-[2-(1 -pyrrolidinyl propyl] -3,5,7-trimethyI-ZH-azepin-Z-one The procedure of Example 5 was followed exceptthat in place of N-(2-chloroethyl)pyrrolidine, there was usedN-(2-chloro-1-methylethyl)pyrrolidine (35.4 g. of a 50% toluenesolution; equivalent to 0.12 mole of halide). There was obtained 24.1 g.of 1,3-dihydro-1-[2-(l-pyrrolidinyl) propyl]-3,5,7-trimethyl-2H-azepin-2-one; B.P. 129- 150 C. at 0.3 mm.; 111.5233.

EXAMPLE 8 1,3-dihydro-1 -(2-m0rph0lin0ethyl) -3,5,7-trimethyl-ZH-azepin-Z-one The procedure of Example 5 was followed except that inplace of N-(Z-chloroethyl)pyrrolidine, there was usedN-(2-chloroethyl)morpholine (36.0 g. of a 50% toluene solution;equivalent to 0.12 mole of halide). There was obtained 20.6 g. of1,3-dihydro-1-(2-morpholinoethyl)- 3,5,7-trimethyl-2H-azepin-Z-one; B.P.ISO-158 C. at 0.15 mm.; 11 1.5233.

EXAMPLE 9 1,3-dihydr0-1-(3-piperidinopropyl) -3,5,7-trimethyl-ZH-azepin-Z-one The procedure of Example 5 was followed except that inplace of N-(2-chloroethyl)pyrrolidine, there was usedN-(S-chloropropyl)piperidine (38.8 g. of a 50% toluene solution;equivalent to 0.12 mole of halide). There was obtained 17.6 g. of1,3-dihydro-1-(3-piperidinopropyl)- 3,5,7-trimethyl-2H-azepin-2-one;B.P. 146157 C. at 0.15 mm.; 21 1.5191.

EXAMPLE 10 1,3-dihydr0-1- [2- (1 -hexahydr0azepinyl) ethyl]3,5,7-trimethyI-ZH-azepin-Z-one The procedure of Example 5 was followedexcept that in place of N-(2-chloroethyl)pyrrolidine, there was usedN-(2-chloroethyl)hexahydroazepine (38.8 g. of a 50% toluene solution;equivalent to 0.12 mole of halide). There was obtained 23.7 g. of1,3-dihydro-1-[2-(1-hexahydroazepinyl)ethyl]-3,5,7-trimethyl 2Hazepin-Z-one; B.P. 136-164 C. at 0.20 mm.; 11 1.5244.

Following the procedure of Example 5 but substituting for thecombination of l,3-dihydro-3,5,7-trimethyl-2H- azepin-Z-one andN-(2-chloroethyl)pyrrolidine as reactants,

1,3-dihydro-3,7-dimethyl-2H-azepin-2-one plus N-( 2-bromoethyl)aziridine;

1,3-dihydro-3,7-diethyl-2I-I-azepin-Z-one plus N-(3-iodopropyl)azetidine;

1,3-dihydro-3,7-dipropyl-2H-azepin-2-one plus N- (4-chlorobutyl)-2-isohexylpyrrolidine 1 9 1,3-dihydro-3,7-diisopropyl-2H-azepin-2-oneplus N-( 5-chloro-2-methylpentyl) -3,4-dioctylpyrrolidine;1,3-dihydro-3,7-diisobutyl-ZH-azepin-Z-one plusN-(2-bromoethyl)-2-methylpiperidine;1,3-dihydro-3,7-dibutyl-2H-azepin-2-one plusN-(4-chlorobutyl)-3-isopropylpiperidine;1,3-dihydro-3,5,7-triethyl-2H-azepin-2-one plusN-(3-iodopropyl)-2-methyl-5-ethylpiperidine;1,3-dihydro-3,7-diethyl-5-methyl-2H-azepin-2-one plus N- 3-chlorol-methylpropyl) -3,3 -dimethylhexahydroazepine;1,3-dihydro-3,7-dimethyl-5-ethyl-2H-azepin-2-one plusN-(2-brornoethyl)heptamethylenimine; 1,3-dihydro-5-tertbutyl-3,7-dimethyl-ZH-azepin-Z-one plus N-(3-iodopropyl)octamethylenimine; 1,3-dihydro-3,7-diisopropyl-5-methyl-2H-azepin-2-oneplus N-(4-chloro-1-methylpentyl) -3,3-dimethylmorpholine; and1,3-dihydro-5-sec-butyl-3,7-dimethyl-2H-azepin-2-one plusN-(Z-bromopropyl)thiomorpholine,

there are obtained 1,3-dihydro-1-[2-( l-aziridinyl) ethyl]-3,7-dirnethyl- 2H-azepin-2-one;

1,3-dihydro-1- [3-( l-azetidinyl) propyl] -3 ,7-diethy1-2H-azepin-Z-one;

1,3-dihydro- 1- [4- Z-isohexyll-pyrrolidinyl butyl] -3,7-

dipropyl-ZH-azepin-Z-one;

1,3-dihydro-1- [5-( 3,4-dioctyl-l-pyrrolidinyl) -4-methylpentyl]-3,7-diisopropyl-2H-azepin-2-one;

1,3-dil1ydro- 1- [2- 2-methylpiperidino) ethyl]-3,7-diisbutyl-2H-azepin-2-one;

1,3-dihydrol- [4- 3-isopropylpiperidino) butyl]-3,7-dibutyl-2H-azepin-2-one1,3-dihydro-1-[3-(2-methyl-5-ethylpiperidino) propyl]-3,

5,7-triethy1-2H-azepin-Z-one;

1,3-dihydro- 1- 3- 3 ,3-dimethyll-hexahydroazepinyl butyl] -3,7-diethyl--methyl-2H-azepin-Z-one;

1,3-dihydro- 1- [2-( l-heptamethylenimino) ethyl] -3,7-di

methyl-5-ethyl-2H azepin-2-one;

1,3-dihydro-1-[3-(1-octamethylenimino)propyl]-5-tertbutyl-3,7-dimethyl-2H-azepin-2-one;

1,3-dihydro-1-[1-methyl-4-(3,3-dimethylmorpholino)pentyl]-3,7-diisopropyl-S-methyl-ZHaazepin-Z-one;and

1,3 -dihydro-1-( 1-methyl-2-thiomorpholinoethyl) -5-secbutyl-3,7-dimethyl-2H-azepin-2-one,

respectively.

EXAMPLE 11 1,3-dihydr0-3,5,7-trimethyl-2H-azepine1,3-dihydro-3,5,7-trimethyl-2H-azepin-2 -one (15.1 g.; 0.10 mole) wasadded in four portions to a stirred slurry of lithium aluminum hydride(2.84 g.; 0.075 mole) in 150 ml. of anhydrous diethyl ether at about 25C. during minutes. The resulting mixture was refluxed with stirring for3 hours while a slow stream of nitrogen was passed into the reactionflask. The reaction mixture was then cooled externally with ice and,with continued stirring, 3 ml. of water, 3 ml. of 25% aqueous sodiumhydroxide solution, and 8 ml. of water were added in that order.Stirring was continued for about 5 minutes. The granular precipitate oftaluminate salts was removed by filtration, and the filtrate wasevaporated to give 1,3- dihydro-3,5,7-trimethyl-2H-azepine in the formof a very fluify, white solid which appeared to be rather unstable.

Following the procedure of Example 11 but substituting for the1,3-dihydro-3,5,7-trimethyl-2H-azepin-Z-one,

1,3-dihydro-3 ,7-dimethyl-ZH-azepin-Z-one; 1,3-dihydro-3,7-diethyl-2Hazepin-2-one; 1,3-dihydro-3,7-dipropyl-ZH-azepin-Z-one1,3-dihydro-3,7-diisopropyl-ZH-azepin-Z-one; 1,3-dihydro-3,7-diisobutyl-2H-azepin-2-one; 1,3-dihydr0-3,5,7 -triethy1-2II-azepin-2-one 20 1,3-dihydro-3,7-diethyl-5-methyl-2H-azepin-2-one;1,3-dihydro-3,7-dimethyl-5-ethyl-2H-azepin-2-one;1,3-dihydro-5-tert-butyl-3,7-dimethyl-ZH-azepin-Z-one; and 1,3-dihydro-3,7 -diisopropyl-S-methyl-ZH-azepin-2-one,

there are obtained 1,3-dihydro-3 ,7-dimethy1-2H-azepine;1,3-dihydro-3,7-diethyl-2H-azepine; 1,3-dihydro-3,7-dipropyl-2H-azepine;

1,3-dihydro-3 ,7-diisopropyl-2H-azepine;1,3-dihydro-3,7-diisobutyl-2H=azepine;1,3-dihydro-3,5,7-triethyl-2H-azepine;1,3-dihydro-3,7-diethyl-5-methy1-2H-azepine;1,3-dihydro-3,7-dimethyl-5-ethyI-ZH-azepine;l,3-dihydro-5-tert-butyl-3,7-dimethyl-2H-azepine; and1,3-dihydro-3,7-diisopropyl-5-methy1-2Hazepine,

respectively.

EXAMPLE 12 I ,3-dihydro-1 ,3,5,7 -tetramethyl-2H -azepine1,3-dihydro-1-,,3,5,7-tetramethyl-2H azepin-2-one (33.0 g.; 0.20 mole)was added in four portions to a stirred slurry .of lithium aluminumhydride (7.6 g.; 0.20 mole) in 200 ml. of anhydrous diethyl ether atabout 25 C. during 10 minutes. The resulting mixture was refluxed withstirring for 3 hours while a slow stream of nitrogen gas was passed intothe reaction flask. The reaction mixture was then cooled externally withice and, with continued stirring, 8 ml. of water, 8 ml. of 25% aqueoussodium hydroxide solution, and 23 ml. of water were added in that order.Stirring was continued for about 5 minutes. The granular precipitate ofinorganic salts was then removed by filtration, and the filtrate wasevaporated to give a pale yellow oil which was distilled under reducedpressure to give 27.7 g. of 1,3-dihydro-1,3,5,7- tetramethyl-ZH-azepinein the form of a colorless liquid which rapidly turned yellow; B.P.50-54 C. at 1.0 mm.

U.V. (diethyl ether) 301 m (=7,050).

LR. (principal bands; CCL; solution) 1635 and 1595 cm.-

EXAMPLE 13 1,3-dihydro-1-ethyl-3,5,7-trimethyl-2H-azepine Following theprocedure of Example 12, 1,3-dihydro-1-ethyl-3,5,7-trimethyl-2H-azepin-2-one (7.7 g.; 0.043 mole) was reactedwith lithium aluminum hydride (1.6 g.; 0.043 mole) to give 5.6 g. of1,3-dihydro-1-ethyl-3,5-7-trimethyl-2H-azepine in the form of acolorless liquid which slowly turned yellow; B.P. 6164 C. at 1 mm.; 111.5176.

U.V. (diethyl ether) 305 mu (E=7,500).

I.R. (principal bands; CCl solution) 1635 and 1585 cmf Following theprocedure of Example 12 but substituting for the1,3-dihydro-1,3,5,7-tetramethyl-2H-azepin-2- one,

1,3-dihydro- 1-allyl-3,5 ,7 -trirnethyl-2H-azepin-Z-one;

1,3 -dihydro- 1-cyclopenty1-3,5,7-trimethyl-2H-azepin-Z- one;

1,3-dihydro-1-benzyl-3,7-diethyl-2H-azepin-2-one;

1,3-dihydro1-(4-tert-butylcyclohexyl)-3,7-diisopropyl- ZH-azepin-Z-one;

1,3-dihydro-3,7-dipropyl-1-hexy1-2H-azepin-2-one; and

1,3-dihydro-l- 2-propynyl) -3,5,7-triethy1-2H-azepin-2- one,

there are obtained 1,3-dihydro-1-allyl-3 ,5 ,7-trimethyl-2H-azepine;

1,3-dihydro-1-cyclopentyl-3,5,7-trimethyl-2H-azepine;

1,3-dihydro-1-benzyl-3,7-diethyl-ZH-azepine;

1,3-dihydro-1-(4-tert butylcyclohexyl) -3,7-diisopropy1- 2H-azepine;

21 1,3-dihydro-3,7-dipropyl-l-hexyl-ZH-azepine; and 1,3-dihydro-1-(2-propynyl) -3,5,7-triethyl-2H-azepine, respectively.

EXAMPLE 14 1,3-dihydr-1- (Z-diethylaminoethyl) -3,5,7-trimethyl-ZH-azepine Following the procedure of Example 12, 1,3-dihydro- 1(Z-diethylaminoethyl)-3,5,7-trimethyl-2H-azepin-2-one (7.5 g.; 0.03mole) was reacted with lithium aluminum hydride (1.15 g.; 0.03 mole) togive 1,3-dihydro-l-(2- diethylaminoethyl)-3,5,7-trimethyl-2H-azepine.

EXAMPLE 15 1,3-dihydr0-1-(3-dimethylaminopr0pyl) -3,5,7-trimethyl-ZH-azepz'ne Following the procedure of Example 12, 1,3-dihydro- 1 (3-dimethylaminopropyl)-3,5,7-trimethyl-2H-azepin- 2-one (7.1 g.; 0.03mole) was reacted with lithium aluminum hydride (1.15 g.; 0.03 mole) togive 1,3-dihydro 1 (3 dimethylaminopropyl) 3,5,7-trimethyl-2H- azepine.

Following the procedure of Example 14 but substituting for the1,3dihydro-1-(2-diethylaminoethy1)-3,5,7- trimethyl-2H-azepin-2-one,

1,3-dihydro-1- (4-dimethylaminobutyl) -3,5,7-trimethyl- 2H-azepin-2-one;

1,3 -dihydro-1-( 6-dihexylaminohexyl -3,5,7-tr-imethy1- 2H-azepin-2-one;

1,3-dihydro-1-(Z-dipentylaminoethyl) -3,7-diethyl-2H- azepin-Z-one;

1 ,3-dihydro-1- dimethylaminopentyl) -3,5 ,7-triethyl- ZH-azepin-Z-one;and

1, 3 -dihydro- 1- 1-methyl- 4- (N-methylethylamino) pentyl] -3,7-dimethyl-5 -ethyl-2H-azepin-2 one,

there are obtained 1,3 -dihydro-1- (4-dimethylaminobutyl) -3 ,5,7-trimethyl- 2H-azepine;

1,3 -dihydro-1- G-dihexylaminohexyl) -3 ,5 ,7-trimethyl- ZH-azepine1,3-dihydro-1- (Z-dipentylaminoethyl) -3 ,7-diethy1-2H- azepine;

1,3-dihydro-1- 5 -dimethylaminopentyl) -3,5,7-triethyl- 2H-azepine; and

1,3-dihydro-1-[1-methyl-4-(N-methylethylamino)pentyl]- 3,7-dimethyl-S-ethyl-ZH-azepine,

respectively.

EXAMPLE 16 1,3-dihydr0-1-(Z-morpholinoethyl)-3,5,7-trimethyl- ZH-azepineFollowing the procedure of Example 12, 1,3-dihydro- 1 (2morpholinoethyl)-3,5,7-trirnethyl-2H-azepin-2-one (7.0 g.; 0.0275 mole)was reacted with lithium aluminum hydride (1.05 g.; 0.0275 mole) to give1,3-dihydro-1-(2- morpholinoethyl) -3 5 ,7-trimethyl-2H-azepine.

EXAMPLE 17 1,3-dihydr0-1- [2 (1 -pyrr0lidinyl ethyl] -3,5,7-trimethyl-ZH-azepine 22 give 1,3 dihydro 1-[2-(2,2,4-trimethyl-l-pyrrolidinyl)ethyl] -3 ,5,7-trimethyl-2H-azepine.

EXAMPLE 19 1,3-dihydro-1- [Z-(I-pyrrolidinyl) propyl] -3,5,7-trimethyl-ZH-aZepine Following the procedure of Example 12, 1,3-dihydro- 1[2-(l-pyrrolidinyl)propyl]-3,5,7-trimethyl-2H-azepin- 2-one (7.9 g.;0.03 mole) was reacted with lithium aluminum hydride 1.15 g.; 0.03 mole)to give 1,3-dihydro-1- [2-( l-pyrrolidinyl)propyl]-3,5,7-trimethyl-2H-azepine.

EXAMPLE 20 1,3-dihydro-1- (3-piperidinopropyl) -3,5,7-trimethyl-ZH-azepine Following the procedure of Example 12, 1,3-dihydro- 1 (3piperidinopropyl)-3,5,7-trimethyl-2H-azepin-Z-one (8.3 g.; 0.03 mole)was reacted with lithium aluminum hydride (1.15 g.; 0.03 mole) to give1,3-dihydro-1-(3- piperidinopropyl -3,5,7-trimethyl-2H-azepine.

EXAMPLE 21 1,3-dihydr0-1- [2- (I-hexahydroazepinyl) ethyl] 3,5, 7-trimthyl-2H -azepine Following the procedure of Example 12, 1,3-dihydro- 1[2 (1 hexahydroazepinyl)ethyl]-3,5,7-trimethyl-2H- azepin-Z-one (8.3 g.;0.03 mole) was reacted with lithium aluminum hydride (1.15 g.; 0.03mole) to give 1,3-dihydro l-[2-( l-hexahydroazepinyl)ethyl]3,5,7-trimethyl- ZH-azepine.

Following the procedure of Example 16 but substituting for the1,3-dihydro-1-(Z-morpholinoethyl)-3,5,7-trimethyl-2H-azepin-2-one,

1,3-dihydro-l- [2- l-aziridinyl) ethyl] -3,7-dimethyl-2H- azepin-Z-one;

l,3-dihydro-1-[3-(1-azetidinyl)propyl]-3,7-diethyl-2H- azepin-Z-one;

1,3-dihydro-1- 3- (2-methyl-S-ethylpiperidino) propyl] 3 ,5,7-triethyl-ZH-azepin-Z-one;

1,3-dihydro-1 [2-( l-heptamethylenimino ethyl] -3,7-

dimethyl-S-ethyl-2H-azepin-2-one;

1,3-dihydro-1- 3-( l-octamethylenimino) propyl]-5-tertbutyl-3,7-dimethyl-ZH-azepin-Z-one; and

1,3 -dihydro-1-( 1-methyl-2-thiomorpholinoethyl)-5-secbutyl-3,7-dimethyl-2H-azepin-2-one,

there are obtained 1,3-dihydro-1-[2-( l-aziridinyl)ethyl]-3,7-dimethyl-2H- azepine;

1,3-dihydro- 1- 3-( l-azetidinyl propyl] -3 ,7-diethyl-2H- azepine;

1,3-dihydro-1- [3 (Z-methyl-S-ethylpiperidino) propyl] 3,5,7-triethyl-2H-azepine;

1,3 -dihydro-1-[2-( l-heptamethylenimino ethyl]3,7-dimethyl-S-ethyl-2H-azepine;

1,3-dihydro-1- [3- 1-o ctamethylenimino propyl]-5-tertbutyl-3,7-dimethyl-2H-azepine; and

1,3 -dihydro-1-( 1-methyl-2-thiomorpholinoethyl)-5-secbutyl-3,7-dimethyl-2H-azepine,

respectively.

Also following the procedures of Examples 11 and 12, each of the other1,3-dihydro-ZH-azepin-Z-ones mentioned above is transformed to thecorresponding 1,3-dihydro- 2H-azepine.

EXAMPLE 22 I,4,6-trimethyl-N-phenyl-Z-azabicyclo[3.2.2]non-6-ene-8,9-dz'carb0vcimide A solution of 1,3 dihydro 3,5,7 trimethyl 2H-azepine, prepared according to Example 11 from 15.1 g. (0.10 mole) of1,3 dihydro 3,5,7 trimethyl 2H- azepin-Z-one, in 50 ml. of benzene wasadded in one portion at about 25 C. to a benzene solution (75 ml.) of

N-phenylmaleimide (17.3 g.; 0.10 mole). The initial red color of thereaction mixture rapidly faded to yellow as the exothermic reactionsubsided. The mixture was allowed to stand about 17 hours at about 25 C.The benzene was then evaporated at reduced pressure, and the residueadsorbed on a 750-g. column of Florisil (60- 100 mesh; a magnesiumtrisilicate; obtained from the Floridin Company, Tallahassee, Fla.) andeluted first, with 4000 ml. of hexane, second, with 5000 ml. of amixture of hexane and diethyl ether (9:1), and third, with 7000 ml. ofdiethyl ether. Evaporation of the first eluate gave 4.1 g. ofN-phenylmaleimide. Evaporation of the second eluate gave 3.0 g. of the1,3-dihydro-3,5,7- trimethyl-2H-azepin-2-one. Evaporation of the thirdeluate gave 3.9 g. of a solid; M.P. 121-122.5 C. Two recrystallizationsof this last material from a mixture of diethyl ether and hexane gave1,4,6-trimethyl-N-phenyl 2 azabicyclo[3.2.2]non 6 ene 8,9 dicarboximidein the form of white stars; M.P. 123.5-124.5 C.

Analysis.Calcd. for C H N O C, 73.52; H, 7.14; N, 9.03. Found: C, 73.49;H, 7.00; N, 8.89.

I.R. (principal bands; mineral oil mull) 3320, 1768, 1709 cm."

Gradual addition of an ethereal solution of hydrogen chloride to anethereal solution of 1,4,6 trimethyl N- phenyl 2 azabicyclo[3.2.2]non 6ene 8,9 dicarboximide until fresh additions no longer causedprecipitation, followed by filtration, gave 1,4,6-trimethyl-N- phenyl 2azabicyclo[3.2.2]non 6 ene 8,9 dicarboximide hydrochloride. Whenethereal solutions of sulfuric acid, phosphoric acid, benzoic acid, andsalicylic acid are used in place of ethereal hydrogen chloride, thecorresponding sulfuric, phosphoric, benzoic, and salicylic acid additionsalts are obtained.

Following the procedure of Example 22 but using in place of Nphenylmaleimide, N methylmaleimide; N butylmaleimide; N ptolylmaleimide; and N- (3,5-xylyl)maleimide, there are obtained1,4,6-trimethyl-N-methyl-Z-azabicyclo [3.2.2] non-6-ene-8,9-dicarboximide;

1,4,6-trimethyl-N-butyl-2-azabicyclo [3 .2.2] -non-6-ene-8,9-dicarboximide;

1,4,6-trimethyl-N-p-tolyl-2-azabicyclo 3 .2.2] non-6-ene- 8,9-dicarboximide; and

1,4,6-trimethyl-N- 3 ,5 -xylyl) -2-azabicyclo [3 .2.2] non-6-ene-8,9-dicarboximide,

respectively. Also following the procedure of Example 22, each of theabove dicarboximides is transformed to the corresponding hydrochloric,sulfuric, phosphoric, benzoic, and salicylic acid addition salts.

Following the procedure of Example 22 but substituting for thecombination of 1,3-dihydro-3,5,7-trimethyl- 2H-azepine andN-phenylmaleimide,

1,3-dihydro-3,7-dimethyl-2H-azepine plus N-ethylmaleimide;

1,3-dihydro-3,7-diethyl-2H-azepine plus N-hexylmaleimide;

1,3-dihydro-5-tert-butyl-3,7-dimethyl-2H-azepine plusN-o-tolylmaleimide; and

1,3-dihydro-3,5,7-triethyl-2H-azepine plus N-(2,4-xylyl)maleimide,

there are obtained 1,4-dimethyl-N-ethyl-2-azabicyclo [3.2.2] non-6-ene-8 ,9-dicarb oximide; 1,4-diethyl-N-hexyl-2-azabicyclo 3 .2.2] non-6-ene-8,9-dicarboximide; 6-tert-butyl-1,4-dimethyl-N-o-tolyl-2-azabicyclo [3.2.2]

non-6-ene-8,9-dicarboximide; and1,4,6-triethyl-N-(2,4-xylyl)-2-azabicyclo [3.2.2] non-6ene-8,9-dicarboximide,

respectively.

Also, following the procedure of Example 22, each of the abovedicarboximides is transformed to the corresponding hydrochloric,sulfuric, phosphoric, benzoic, and salicylic acid addition salts.

EXAMPLE 23 1,2,4,6-tetramethyl-N-phenyl-Z-azabicyclo[3.2.2] -non-6-ene-8,9-dicarb0ximide 1,3 dihydro 1,3,5,7 tetramethyl 2H azepine wasprepared according to Example 12 from 8.3 g. (0.05 mole) of 1,3 dihydro1,3,5,7 tetramethyl 2H- azepin-Z-one (dissolved in 25 ml. of diethylether) and 2.1 g. (0.055 mole) of lithium aluminum hydride. The yellowoily product was not distilled but was dissolved in 35 ml. of benzeneand added in one portion at about 25 C. to a dry benzene solution (40ml) of N-phenylmaleimide (8.7 g.; 0.05 mole). The initial red color ofthe reaction mixture rapidly faded to yellow as the exothermic reactionsubsided. The mixture was allowed to stand about 17 hours at about 25 C.The benzene was then evaporated at reduced pressure, and the residualgum adsorbed on a 1000-g. column of Florisil (60100 mesh). Elution withdiethyl ether and evaporation of the eluate gave a material which wasrecrystallized from a mixture of diethyl ether and hexane to give 10.3g. of a pink solid; M.P. 94.596 C. Three additional recrystallizationsfrom a mixture of diethyl ether and hexane gave 1,2,4,6 tetramethyl Nphenyl 2- azabicyclo[3.2.2]non 6 ene 8,9 dicarboximide in the form ofstout white prisms; M.P. 9898.5C.

Analysis.-Calcd. for C H N O C, 74.04; H, 7.46; N, 8.64. Found: C,74.39; H, 7.53; N, 8.42.

IR. (principal bands; mineral oil mull) 1768 and 1705 cm.-

Following the procedure of Example 22, the hydrochloride of 1,2,4,6tetramethyl N phenyl 2- azabicyclo[3.2.2]non 6 ene 8,9 dicarboximide wasprepared. When ethereal solutions of sulfuric acid, phosphoric acid,benzoic acid, and salicylic acid are used in place of ethereal hydrogenchloride, the corresponding sulfuric, phosphoric, benzoic, and salicylicacid addition salts are obtained.

EXAMPLE 24 2-etIzyl-1,4,6-trimetlzyl-N-phenyl-Z-azabicycle [3 .2.2 -n0n-6-ene-8,9-dicarb0ximide 1,3 dihydro 1 ethyl 3,5,7 trimethyl 2H azepinewas prepared according to Example 13 from 7.8 g. (0.043 mole) of 1,3dihydro 1 ethyl 3,5,7 trimethyl 2H- azepin-Z-one and 1.82 g. (0.048mole) of lithium aluminum hydride. The product was not distilled but wasdissolved in 30 ml. of benzene and added in one portion to a dry benzenesolution (50 ml.) of N-phenyl-maleimide (7.5 g.; 0.043 mole). Theinitial red color of the reaction mixture rapidly faded as theexothermic reaction subsided. The mixture was allowed to stand about 17hours at about 25 C. The benzene was then evaporated at reducedpressure. The residue crystallized on addition of about 10 ml. ofdiethyl ether. Filtration gave 11.1 g. of a greyish solid; M.P. -148 C.Recrystallization from ethyl acetate gave 2 ethyl 1,4,6 trimethyl- Nphenyl 2 azabicyclo[3.2.2]non 6 ene 8,9- dicarboximide in the form ofstout white prisms; M.P. 149-150 C.

Analysis.Calcd. for C H N O C, 74.52; H, 7.74; N, 8.28. Found: C, 74.76;H, 8.02; N, 8.17.

IR. (principal bands; mineral oil mull) 1768 and 1705 cur- Following theprocedure of Example 22, the hydrochloride of2-ethyl-l,4,6-trimethyl-N-phenyl-2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide was prepared. When ethereal solutionsof sulfuric acid, phosphoric acid, benzoic acid, and salicylic acid areused in place of ethereal hydrogen chloride, the corresponding sulfuric,phosphoric, benzoic, and salicylic acid addition salts are obtained.

Following the procedure of Example 23 or Example 24 but substituting forthe particular combination of the 1,3-dihydro-2H-azepine and themaleimide used therein,

1,3-dihydro-1-allyl-3,5,7-trimethyl-2H-azepine plus N-propylmaleimide;1,3-dihydro-1-cyclopentyl-3,5,7-trimethyl-2H-azepine plusN-sec-butylmaleimide; 1,3-dihydro-1-benzy1-3,7-diethyl-2H-azepine plusN-p-ethylphenylmaleimide;1,3-dihydro-1-(4-tert-butylcyclohexyl)-3,7-diisopropyl- 2H-azepine plusN-m-isopropylphenylmaleimide;1,3-dihydro-3,7-dipropyl-l-hexyl-ZH-azepine plus N-(2,4-xylyl)maleimide;and 1,3-dihydro-1-(2-propynyl) -3,5,7-triethyl-2H-azepine plusN-phenylmaleimide,

there are obtained 2-allyll ,4,6-trimethyl-N-propyl-2-azabicyclo [3.2.2]non- 6-ene-8,9-dicarb oximide;

2-cyclopentyl-1,4, 6-tri'methyl-N-sec-butyl-2-az abicyclo [3 .2.2]non-6-ene-8,9-dicarboximide;

2-benzyl-1,4-diethyl-N-p-ethylphenyl-Z-azabicyclo [3 .2.2]non-6-ene-8,9-dicarboximide;

2-(4-tert-butylcyclohexyl)-1,4-diisopropyl-N-m-isopropylphenyl-Z-azabicyclo [3.2.2] non-6-ene-8,9-dicarboximide;

1,4-dipropyl-2-hexyl-N-(2,4-xyly1) -2-azabicyclo [3 .2.2]

non-6-ene-8,9-dicarboximide; and

2-(2-propynyl) -1,4,6-triethyl-N-phenyl-2-azabicyclo [3.2.2]non-6-ene-8,9-dicarboximide,

respectively. Also, following the procedure of Example 22, each of theabove dicarboximides is transformed to the corresponding hydrochloric,sulfuric, phosphoric, benzoic, and salicyclic acid addition salts.

EXAMPLE 25 2- (Z-diethy lamino ethyl) -1,4,6-trim'ethyl-N-phenyl-Z-azabicyclo [3 .2.2 non-6-ene-8,9-dicarb0ximide A solution ofN-phenylmaleimide (5.2 g.; 0.03 mole) in ml. of benzene was added atabout 25 C. to a benzene solution (25 ml.) of1,3-dihydro-1-(2-diethylaminoethyl)- 3,5,7-trimethyl-2H-azepine,prepared according to Example 14 from 7.5 g. (0.03 mole) of1,3-dihydro-1-(2- diethylaminoethyl)-3,5,7-trimethyl-ZH-azepin-Z-one.The initial red color of the reaction mixture rapidly faded to yellow asthe exothermic reaction subsided. The mixture was allowed to stand about17 hours at about 25 C. The benzene was then evaporated at reducedpressure and the residual oil was dissolved in 6 normal hydrochloricacid. This aqueous acid solution was extracted with methylene chlorideand then, with external cooling, was made basic with concentratedaqueous ammonia solution. The basic mixture was extracted with three250-ml. portions of methylene chloride, and the combined extracts weredried, filtered, and evaporated to giveZ-(Z-diethylaminoethyl)-1,4,6-trimethyl-N-phenyl-2- azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide in the form of an oil. This oil wasdissolved in diethyl ether and to this solution was added etherealhydrogen chloride until no further precipitate formed. Filtration gave11.4 g. of a pale yellow powder; M.P. 163-169 C. Recrystallization froma mixture of water and acetone gave 2-(2- diethylaminoethyl) 1,4,6trimethyl N phenyl 2- azabicyclo [3.2.2]non 6 ene-8,9-dicarboximidedihydrochloride in the form of white prisms; M.P. 183 C.

Analysis.Calcd. for C25H3'7Cl2N O2: C, H, 7.73; N, 8.71. Found: C,62.60; H, 8.03; N, 8.51.

I.R. (principal bands; mineral oil mull) 1770 and 1710 cmf Use of onemole of hydrogen chloride per mole of dicarboximide rather than 2 ormore moles of hydrogen chloride gives the monohydrochloride. Use ofsulfuric acid, phosphoric acid, benzoic acid, and salicyclic acid inplace of the hydrogen chloride gives the corresponding sulfuric,phosphoric, benzoic, and salicylic monoand diacid addition salts.

EXAMPLE 26 2- (S-dimethylamz'nopropyl) -1,4,6-lrimethyl-N-phenyl-2-azabicyclo[3.2.2]lz-on-6-ene-8,9-dicarb0ximide Following the procedureof Example 25 but using the 1,3 dihydro 1 (3 dimethylaminopropyl) 3,5,7trimethyl-ZH-azepine prepared according to Example 15 in place of1,3-dihydro-1-(2-diethylaminoethyl)-3,5,7-trimethyI-ZH-azepine, therewere obtained 2-(3-dimethylaminopropyl) 1,4,6 trimethyl N phenyl 2azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide and its dihydrochloride.

Following the procedure of Example 25 but substituting for theparticular combination of the 1,3-dihydro-2H- azepine and the maleimideused therein,

1,3-dihydro-1-( 4-dimethylaminobutyl)-3,5,7-trimethyl- 2H-azepine plusN-methylmaleimide;

1,3-dihydro-1-(fi-dihexylarninohexyl)-3,5,7-trimethyl- 2H-azepine plusN-pentylmaleimide;

1,3-dihydro-1-(Z-dipentylaminoethyl)-3,7-diethyl- ZH-azepine plusN-p-tolylmaleimide;

1,3-dihydro-l-(S-dimethylaminopentyl)-3,5,7-triethyl- ZH-azepine plusN-p butylphenylmaleimide; and

1,3-dihydro-l-[1methyl-4-(N-methylethylamino)pentyl]-3,7-dimethyl-5-ethyI-ZH-azepine plus N-(2,5- xylyl) maleimide,

there are obtained 2-(4-dimethylaminobutyl)-1,4,6-trirnethyl-N-methyl-2-azabicyclo [3 .2.2] non-6-ene-8,9-dicarboximide 2- (6-dihexylaminohexyl)-3 ,5 ,7-trimethyl-N-pentyl-2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide;

l,4-diethyl-2-(Z-dipentylaminoethyl)-N-p-tolyl-2- azabicyclo [3 .2.2]non-6-ene-8,9-dicarboximide;

2-(S-dimethylaminopentyl) -1,4,6-triethyl-N-p-butylphenyl-Z-azabicyclo[3 .2.2]non-6-ene-8,9- dicarboximide; and

1,4-dimethyl-6-ethyl-2- 1-methy1-4- (N-methylethylamino -pentyl] -N- 2,5-xylyl) -2-azabicyclo [3 .2.2] non- 6-ene-8,9-dicarboximide,

respectively. Also following the procedure of Example 25, each of theabove dicarboximides is transformed to the corresponding hydrochloric,sulfuric, phosphoric, benzoic, and salicylic acid addition salts.

EXAMPLE 27 2 (2 morpholinoethyl) 1,4,6 trimethyl N phenyl- Z-azabicyclo[3.2.2]non-6-erte-8,9-dicarboximide A solution of N-phenylmaleimide(4.75 g.; 0.0275 mole) in 35 ml. of benzene was added at about 25 C. toa benzene solution (25 ml.) of1,3-dihydro-1-(2-morpholinoethyl)-3,5,7-trimethyl-2H-azepiue, preparedaccording to Example 16 from 7.0 g. (0.0275 mole) of 1,3- dihydro 1 (2morpholinoethyl)-3,5,7-trimethyl-2H- azepine-Z-one. The initial deep redcolor of the reaction mixture faded rapidly to pale orange as theexothermic reaction subsided. The mixture was allowed to stand about 17hours at about 25 C. Following the procedure of Example 25, the desiredadduct was isolated in free base form and transformed to a pale yellowdihydrochloride; yield 10.8 g.; M.P. 174-180 C. Recrystallization from amixture of water and acetone gave 2-(2-morpholinoethyl) 1,4,6trimethyl-N-phenyl-2-aza'bicyclo- [3.2.2]non 6-ene-8,9-dicarboximidedihydrochloride in the form of white prisms; M.P. -186 C.

Analysis.Calcd. for C H Cl N O C, 60.48; H, 7.11; N, 8.46. Found: C,60.10; H, 7.35; N, 8.30.

IR. (principal bands; mineral oil mull) 1775 and 1710 cm.-

Use of one mole of hydrogen chloride per mole of dicarboximide ratherthan two or more moles of hydrogen chloride gives the monohydrochloride.Use of sulfuric acid, phosphoric acid, benzoic acid, and salicylic acidin place of the hydrogen chloride gives the corresponding sulfuric,phosphoric, benzoic, and salicylic monoand diacid addition salts.

EXAMPLE 28 2- [2-(1-pyrr0lidilzyl) ethyl] -1,4,6-trimethyl-N-p-tolyl-Z-azabicyclo [3.2.2] non-6-ene-8,9-dicarboximide Following the procedureof Example 27, the 1,3- dihydro 1 [2(1-pyrrolidinyl)ethyl]-3,5,7-trimethyl- 2H-azepine obtained in Example17 was reacted with N-p-tolylmaleimide to give2-[2-(1-pyrrolidinyl)ethyl]- 1,4,6trimethyl-N-p-tolyl-2-azabicyclo[3.2.2] non-6-ene- 8,9-dicarboximide andits dihydrochloride.

EXAMPLE 29 2 [2 (2,2,4 trimetIzyl-I-pyrrolidinyl)ethyl]-1,4,6-lrimethylN butyl 2 azabicycl[3.2.2]non-6-ene-8,9- dicarboximide Following theprocedure of Example 27, the 1,3- dihydro 1 [2(2,2,4-trimethyl-1-pyrrolidinyl)ethyl]- 3,5,7-trimethyl-2H-azepineobtained in Example 18 was reacted with N-butyl-maleimide to give2-[2-(2,2,4-trimethyl l-pyrrolidinyl ethyl] -l,4,6-trimethyl-N-butyl-2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide and its dihydrochloride.

EXAMPLE 30 2 [2(I-pyrrolidz'nyl)propyl]-1,4,6-trimethyl-N-p-ethylphenyl-2-azabicyclo[3.2.2]Iz0n-6-ene-8,9-dicarb0ximideFollowing the procedure of Example 27, the 1,3- dihydro 1 [2(1-pyrrolidinyl)propy1]-3,5,7-trimethyl- ZH-azepine obtained in Example19 was reacted with N-pethylphenylmaleimide to give 2 [2 (1pyrrolidinyl) propyl] 1,4,6 trimethyl-N-p-ethylphenyl-2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide and its dihydrochloride.

EXAMPLE 31 2-(3-piperidinopr0pyl) -1,4,6-trimethyl-N-hexyl-Z- azabicyclo[3.2.2] n0n-6-ene-8,9-dicarb0ximide Following the procedure of Example27, the 1,3- dihydro 1 (3 piperdinopropyl)-3,5,7-trimethyl-2H- azepineobtained in Example 20 was reacted with N- hexylmaleimidc to give 2(3-piperidinopropyl)-1,4,6- trimcthyl N hexyl 2azabicyclo[3.2.2]non-6-ene- 8,9-dicarboximide and its dihydrochloride.

EXAMPLE 32 2 [2 (1 hexahydroazepinyl)ethyl]-],4,6-trimethyl-N- (2,4xylyl) 2 azabicyclo[3.2.2]n0n-6-ene-8,9-dicarboximide Following theprocedure of Example 27, the 1,3- dihydro 1 [2(l-hexahydroazepinyl)ethyl]-3,5,7-trimethyI-ZH-azepine obtained inExample 21 was reacted with N-(2,4-xylyl)maleimide to give2-[2-(1-hexahydroazepinyl)ethyl] 1,4,6trimethyl-N-(2,4-xylyl)-2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximideand its dihydrochloride.

Following the procedure of Example 27, but substituting for theparticular combination of the 1,3-dihydro-2H- azepine and the maleimideused therein,

1,3 -dihydro-1-[2-( l-aziridinyl ethyl] -3,7-dimethyl-2H- azepine plusN-methylmaleimide;

1,3 -dihydro- 1- [3 1-azetidinyl)propyl] -3 ,7 -diethyl-2H- azepine plusN-isohexylmaleimide;

1,3 -dihydro-l- [3 Z-methyl-S-ethylpiperidino propyl]3,5,7-triethyl-2H-azepine plus N-p-isopropylphenylmaleimide;

1,3 -dihydro-l [2( l-heptamethylenimino) ethyl] -3 ,7-

dimethyl--ethyl-2H-azepine plus N-o-tolylmaleimide;

1,3 -dihydro- 1- [3 l-octamethylenimino pro pyl] -5 -tertlbutyl-3,7 dimethyl-2H-azcpine plus N-(2,4-xylyl) maleimide; and

1,3 -dihydro-1-(1-methyl-2-thiomorpholinoethyl)-5-sec- 2sbutyl-3,7-dimethyl-2H-azepine plus N-(3,5-diethylphenyDmaleimide,

there are obtained 2- 2- l-aziridinyl) ethyl] -1 ,4-dimethyl-N-methyl-2-azabicyclo [3 .2.2] non-6-ene-8,9-dica rboximide;

2-[3-(1-azetidinyl)propyl]-l ,4-diethyl-N-isohexyl-2- azobicyclo [3.2.2] -non-6-ene-8,9-dicarboximide;

2- 3-( 2-methyl-5 -ethy1piperidino) -propyl] 1,4,6-tricthyl-N-p-isopropylphenyl-2-azabicyclo [3 .2.2] -non-6-ene- 8,9-dicarboximide;

2- [2-( l-heptamethylenimino) ethyl] -1 ,4-dimethyl-6-ethyl-N-o-tolyl-2-azabicyclo[3 .2.2)non-6-ene-8,9- dicarboximide2-[3-(1-octamethylenhnino)propyl]-6-tert-butyl-1,4-

dimethylN-(2,4-xylyl)-2-azabicyclo[3.2.2]non-6-ene- 8,9-dicarboximide;and

2-(1-methyl-2-thiomorpholinoethyl)-6-scc-butyl-1,4-

dimethyl-N- 3,5 -diethylphenyl) -2-az'abicyclo- [3 .2.2]non-6-ene-8,9-dicarb ox'imide, respectively,

as well as the monoand dihydrochlorides of each of these dicarboximides.Following the procedure of Example 27, the dicarboximides of Examples28, 29, 30, 31 and 32 as well as each of the other dicarboximidesmentioned above after Example 32 is transformed to the correspondingsulfuric, phosphoric, benzoic, and salicylic acid monoand diacidaddition salts.

EXAMPLE 33 2-acetyl-1,4,6-trimethyl-N-phenyl-Z-azabicyclo-[3.2.2]-

non-6-ene-8,9-dicarb0ximide A mixture of1,4,6-trimethyl-N-phenyl-2-azabicyclo-[3.2.2]-non-6-ene-8,9-dicarboximide (0.96 g.; 0.003 mole) and aceticanhydride (5.0 ml.; 4.6 g.; 0.045 mole) was protected from atmosphericmoisture with a tube of calcium chloride and was heated at about C. for2 hours. The resulting solution was allowed to stand at about 25 C. forabout 17 hours. The crystals which separated were filtered, washed withhexane, and dried to give 1.0 g. of a solid; M.P. 226.5-228 C.Recrystallization from a mixture of water and acetic acid gave 2- acetyl1,4,6 trimethyl N phenyl 2 azabicyclo-[3.2.2]non-6-ene-8,9-dicarboximide in the form of white prisms; M.P.229-230.5 C.

for C21HZ4N203: C, H, N, 7.95. Found: C, 71.91; H, 7.03; N, 7.79.

I.R. (principal bands; mineral oil mull) 1768, 1710, 1656, 1639 cm.-

Following the procedure of Example 33 but using in place of aceticanhydnide, propionic anhydride; butyric anhydride; isobutyric anhydride;Valerie anhydride; and the mixed anhydride of formic and acetic acids,there are obtained 2-propionyl-1,4,6-trimethyl-N-phenyl-2-azabicyclo-[3.2.2] non-6-ene-8,9-dicarboximide;Z-butyryl-1,4-6-tnimethyl-N-phenyl-Z-azabicyclo [3.2.2]

non-6-ene-8,9-dicarboximide;2-isobutyryl-1,4,6-trimethyl-N-phenyl-2-azabicycl0 [3 .2.2]non-6-ene-8,9-dicarboxi'mide; 2-valeryl- 1,4,6-trimethyl-N-phenyl-2-azabicyclo [3 .2.2]

non-6-ene-8,9-dicarboximide; and2-formyl-1,4,6-trimethyl-N-phenyl-Z-azabicyclo[3 .2.2]-

non-6-ene-8,9-dicarboximide, respectively.

Following the procedure of Example 33 but using in place of thecombination of 1,4,6-trimethyl-N-phenyl-2-azabicyclo[3.2.2]-non-6-ene-8,9-dicarboximide and acetic anhydride,

1,4,6-trimethyl-N-m'ethyl-2-azabicyolo[3.2.2]non-6-ene-8,9-dicarboximide plus the mixed anhydride of formic and acetic acids;

1,4-dimcthyl-N-ethyl-2-azabicyclo[3.2.2]non-6-enc-8,9-

dicarboximide plus acetic anhydride;

29 1,4-diethyl-N-hexyl-2-azabicyclo[3.2.2]non6-ene-8,9-

dicarboximide plus propionic anhydride;6-tert-butytl-1,4-dimethyl-N-o-tolyl-2-azabicyclo [3 .2.2

non-6-ene-8,9-dicarboximide plus butyric anhydride; andl,4,6-triethyl-N-( 2,4-xyly1) -2-azabicyclo [3 .2.2 non-6-ene-8,9-dicarboxirnide plus acetic anhydride,

the re are obtainedZ-formyl-1,4,6-trimethyl-N-methyl-2-azabicyclo[3.2.2]

non-6-ene-8,9-dicarboximide;Z-acetyl-1,4-dimechyl-N-ethyl-2-azabicyclo[3 .2.2]non-6-ene-8,9-dicarboximide; l,4-diethyl-N-hexyl-2-propionyl-2-azabicyclo [3.22] non- 6-ene-8,9-dicarboximide;6-tertbutyl-2-butyryl-1,4-dimethyl-N-o-tolyl-2-azabicyolo[3.2.2]non-6-ene-8,9-dicarbox-imide; andZ-acetyl-l,4,6-triethyl-N-(2,4-xy1yl) -2-azabicyclo [3.2.2]

non-6-ene-8,9dicarboximide, respectively.

I claim:

1. A compound selected from the group consisting of the free base formand acid addition salts of a compound of the formula:

wherein R and R are alkyl of 1 to 4 carbon atoms, inclusive, wherein Ris selected from the group consisting of hydrogen and alkyl of 1 to 4carbon atoms, inclusive, wherein R is selected from the group consistingof hydrogen, lower alkyl, alkenyl of 3 to 6 carbon atoms, inclusive,alkynyl of 3 to 6 carbon atoms, inclusive, cycloalkyl of to 10 carbonatoms, inclusive and aralkyl of 7 to 11 carbon atoms, inclusive, andwherein R is selected from the group consisting of lower alkyl, phenyl,loweralkylphenyl, and di-lower-alkylphenyl.

2. 1,4,6-trimethyl-Nphenyl 2 azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide.

3. 1,2,4,6 tetramethy-l N phenyl 2 azabicyclo-[3.2.2]non--ene-8,9-dicarboximide.

4. 2 ethyl 1,4,6 trimethyl N phenyl 2 azabicyclo [3 .22]non-6-ene-8,9-dicarbox-imide.

5. A process for producing a 2-azabicyclo[3.2.2]non-6-ene-8,9-dicarboximide of the formula:

wherein R and R are alkyl of 1 to 4 carbon atoms, inelusive, wherein Ris selected from the group consisting of hydrogen and alkyl of 1 to 4carbon atoms, inclusive, wherein R is selected from the group consistingof hydrogen, lower alkyl, alkenyl of 3 to 6 carbon atoms, inclusive,alkynyl of 3 to 6 carbon atoms, inclusive, cycloalkyl of 5 to 10 carbonatoms, inclusive, and aralkyl of 7 to 11 carbon atoms, inclusive, andwherein R is selected from the group consisting of lower alkyl, phenyl,loweralkylph'eny l, and di-lower-alkylphenyl, which comprises mixing acompound of the formula:

wherein R R R and R are as given above, with a maleimide of the formula:

\NR5 HCO/ wherein R is a given above, to form said Z-azabicyclo-[3.2.2]non-6-ene-8,9-dicarboximide.

References Cited by the Examiner UNITED STATES PATENTS 1,915,334 6/1933Salzberg et al 260243 2,075,359 3/1937 Salzberg et a1 167-22 2,362,61411/ 1944 Calva 16722 ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

JOSE TOVAR, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE FREE BASE FORMAND ACID ADDITION SALTS OF A COMPOUND OF THE FORMULA: